Archaeological finds place the eastern border for the prehistoric Martis people in the Reno area. As early as the mid-1850s, a few pioneers settled in the Truckee Meadows, a relatively fertile valley through which the Truckee River made its way from Lake Tahoe to Pyramid Lake. In addition to subsistence farming, these early residents could pick up business from travelers along the California Trail, which followed the Truckee westward, before branching off towards Donner Lake, where the formidable obstacle of the Sierra Nevada began.

Gold was discovered in the vicinity of Virginia City in 1850, and a modest mining community developed, but the discovery of silver in 1859 at the Comstock Lode led to a mining rush, and thousands of emigrants left their homes, bound for the West, hoping to find a fortune.

To provide the necessary connection between Virginia City and the California Trail, Charles W. Fuller built a log toll bridge across the Truckee River in 1859. A small community that served travelers soon grew near the bridge. After two years, Fuller sold the bridge to Myron C. Lake, who continued to develop the community by adding a grist mill, kiln, and livery stable to the hotel and eating house. He renamed it "Lake's Crossing". Most of what is present-day western Nevada was formed as the Nevada Territory from part of Utah Territory in 1861.

By January 1863, the Central Pacific Railroad (CPRR) had begun laying tracks east from Sacramento, California, eventually connecting with the Union Pacific Railroad at Promontory, Utah, to form the First Transcontinental Railroad. Lake deeded land to the CPRR in exchange for its promise to build a depot at Lake's Crossing. In 1864, Washoe County was consolidated with Roop County, and Lake's Crossing became the county's largest town. Lake had earned himself the title "founder of Reno". Once the railroad station was established, the town of Reno officially came into being on May 9, 1868. CPRR construction superintendent Charles Crocker named the community after Major General Jesse Lee Reno, a Union officer killed in the Civil War at the Battle of South Mountain.

In 1871, Reno became the county seat of the newly expanded Washoe County, replacing the county seat in Washoe City. However, political power in Nevada remained with the mining communities, first Virginia City and later Tonopah and Goldfield.

The extension of the Virginia and Truckee Railroad to Reno in 1872 provided a boost to the new city's economy. In the following decades, Reno continued to grow and prosper as a business and agricultural center and became the principal settlement on the transcontinental railroad between Sacramento and Salt Lake City. As the mining boom waned early in the 20th century, Nevada's centers of political and business activity shifted to the nonmining communities, especially Reno and Las Vegas, and today, the former mining metropoles stand as little more than ghost towns. Despite this, Nevada is still the third-largest gold producer in the world, after South Africa and Australia; the state yielded 6.9% of the world's supply in 2005 world gold production.

The Reno Arch was erected on Virginia Street in 1926 to promote the upcoming Transcontinental Highways Exposition of 1927. The arch included the words "Nevada's Transcontinental Highways Exposition" and the dates of the exposition. After the exposition, the Reno City Council decided to keep the arch as a permanent downtown gateway, and Mayor E.E. Roberts asked the citizens of Reno to suggest a slogan for the arch. No acceptable slogan was received until a $100 prize was offered, and G.A. Burns of Sacramento was declared the winner on March 14, 1929, with "Reno, the Biggest Little City in the World".

Reno took a leap forward when the state of Nevada legalized open gambling on March 19, 1931, along with the passage of even more liberal divorce laws than places such as Hot Springs, Arkansas, offered. The statewide push for legal Nevada gaming was led by Reno entrepreneur Bill Graham, who owned the Bank Club Casino in Reno, which was on Center Street. No other state offered legalized casino gaming like Nevada had in the 1930s, and casinos such as the Bank Club and Palace were popular.^{[citation needed]} A few states had legal pari mutuel horse racing, but no other state had legal casino gambling. The new Nevada divorce laws, passed in 1927, allowed people to divorce each other after six weeks of residency, instead of six months. People wishing to divorce stayed in hotels, houses, and/or dude ranches. Most divorcees left Nevada when their divorces were finalized, while some stayed.

Within a few years, the Bank Club, owned by George Wingfield, Bill Graham, and Jim McKay, was the state's largest employer and the largest casino in the world. Wingfield owned most of the buildings in town that housed gaming and took a percentage of the profits, along with his rent.

Ernie Pyle once wrote in one of his columns, "All the people you saw on the streets in Reno were obviously there to get divorces." In Ayn Rand's novel The Fountainhead, published in 1943, the New York-based female protagonist tells a friend, "I am going to Reno," which is taken as a different way of saying "I am going to divorce my husband." Among others, Belgian-French writer Georges Simenon, at the time living in the U.S., came to Reno in 1950 to divorce his first wife.

The divorce business eventually died after about 1970, as the other states fell in line by passing their own laws easing the requirements for divorce, but gambling continued as a major Reno industry. While gaming pioneers such as "Pappy" and Harold Smith of Harold's Club and Bill Harrah of the soon-to-dominate Harrah's Casino set up shop in the 1930s, the war years of the 1940s cemented Reno as the place to play for two decades. Beginning in the 1950s, the need for economic diversification beyond gaming fueled a movement for more lenient business taxation.

A disaster occurred on the afternoon of February 5, 1957, when an explosion ripped through the heart of downtown. At 1:03 pm, two explosions, caused by natural gas leaking into the maze of pipes and ditches under the city, and an ensuing fire, destroyed five buildings in the vicinity of Sierra and First Streets along the Truckee River. The disaster killed two people and injured 49. The first explosion hit under the block of shops on the west side of Sierra Street (now the site of the Century Riverside), the second, across Sierra Street, now the site of the Palladio.^{[citation needed]}

The presence of a main east–west rail line, the emerging interstate highway system, favorable state tax climate, and relatively inexpensive land created good conditions for warehousing and distribution of goods.^{[citation needed]}

In the 1980s, Indian gaming rules were relaxed, and starting in 2000, Californian Native casinos began to cut into Reno casino revenues. Major new construction projects have been completed in the Reno and Sparks areas. A few new luxury communities were built in Truckee, California, about 28 miles (45 km) west of Reno on Interstate 80. Reno also is an outdoor recreation destination, due to its close proximity to the Sierra Nevada, Lake Tahoe, and numerous ski resorts in the region.

In 2018, the city officially changed its flag after a local contest was held.

As of the census of 2010, there were 225,221 people, 90,924 households, and 51,112 families residing in the city. The population density was 2,186.6 per square mile (844.2/km²). There were 102,582 housing units at an average density of 995.9 per square mile (384.5/km²). The city's racial makeup was 74.2% White, 2.9% African American, 1.3% Native American, 6.3% Asian, 0.7% Pacific Islander, 10.5% some other race, and 4.2% from two or more races. Hispanic or Latino people of any race were 24.3% of the population.Non-Hispanic Whites were 62.5% of the population in 2010, down from 88.5% in 1980.

At the 2010 census, there were 90,924 households, of which 29.8% had children under the age of 18 living with them, 38.4% were headed by married couples living together, 11.8% had a female householder with no husband present, and 43.8% were non-families. 32.1% of all households were made up of individuals, and 9.7% were someone living alone who was 65 years of age or older. The average household size was 2.43, and the average family size was 3.10.

In the city, the 2010 population was spread out, with 22.8% under the age of 18, 12.5% from 18 to 24, 28.2% from 25 to 44, 24.9% from 45 to 64, and 11.7% who were 65 years of age or older. The median age was 34.6 years. For every 100 females, there were 103.4 males. For every 100 females age 18 and over, there were 102.7 males.

In 2011 the city's estimated median household income was $44,846, and the median family income was $53,896. Males had a median income of $42,120 versus $31,362 for females. The city's per capita income was $25,041. About 9.6% of families and 14.4% of the population were below the poverty line, including 15.1% of those under age 18 and 12.8% of those age 65 or over. The population was 180,480 at the 2000 census; in 2010, its population had risen to 225,221, making it the third-largest city in the state after Las Vegas and Henderson, and the largest outside Clark County. Reno lies 26 miles (42 km) north of the Nevada state capital, Carson City, and 22 miles (35 km) northeast of Lake Tahoe in a shrub-steppe environment. Reno shares its eastern border with the city of Sparks and is the larger of the principal cities of the Reno–Sparks, Nevada Metropolitan Statistical Area (MSA), a metropolitan area that covers Storey and Washoe counties. The MSA had a combined population of 425,417 at the 2010 census. The MSA is combined with the Fernley Micropolitan Statistical Area and the Carson City MSA to form the Reno-Carson City-Fernley Combined Statistical Area, which had a population of 477,397 at the 2010 census.