Stokes was born in Cleveland, the son of Louise (Stone) and Charles Stokes, a laundryman who died when Carl was three years old. He and his brother, Politician Louis Stokes, were raised by their mother in Cleveland's first federally funded housing project for the poor, Outhwaite Homes. Although a good student, Stokes dropped out of high school in 1944, worked briefly at Thompson Products (later TRW), then joined the U.S. Army at age 18. After his discharge in 1946, Stokes returned to Cleveland and earned his high school diploma in 1947.

He then attended several colleges before earning his bachelor's degree from the University of Minnesota in 1954. He graduated from Cleveland-Marshall College of Law in 1956 and was admitted to the Ohio bar in 1957. While studying law he was a probation officer. For four years, he served as assistant prosecutor and became partner in the law firm of Stokes, Stokes, continuing that practice into his political career; it was successful after one year.

Elected to the Ohio House of Representatives in 1962, he served three terms. Stokes worked hard to even out legislative districts. Then, Ohio had uneven representation among its Congressional and General Assembly districts. By the late 1960s, he was able to carve out a district that could elect him to Congress, but deferred to his brother Louis Stokes who represented Cleveland in the US House of Representatives for three decades. Stokes narrowly lost a bid for mayor of Cleveland in 1965. His victory two years later drew national attention, as he was the first black mayor of one of the ten biggest cities in the United States.

As mayor, Stokes opened city hall jobs to blacks and women. He was known as a strong administrator, and is remembered for his vision and motivation. Stokes feuded with City Council and the Police Department for most of his tenure. He also initiated Cleveland: Now!, a public and private funding program aimed at the revitalization of Cleveland neighborhoods. Stokes pulled through and was reelected in 1969.

After his mayoral administration, Stokes lectured to colleges around the country. In 1972, he became the first black anchorman in New York City when he took a job with television station WNBC-TV. While at WNBC New York, Stokes won a New York State Regional Emmy for excellence in craft, for a piece about the opening of the Paul Robeson play, starring James Earl Jones on Broadway. After accusing NBC of failing to promote him to a national brief, he returned to Cleveland in 1980 and began serving as general legal counsel for the United Auto Workers.

From 1983 to 1994, he served as municipal judge in Cleveland. President Bill Clinton then appointed him U.S. Ambassador to the Republic of Seychelles. Stokes was awarded 12 honorary degrees, numerous civic awards, and represented the United States on numerous goodwill trips abroad by request of the White House. In 1970, the National League of Cities voted him its first black president-elect.

He was on an episode of Eyes on the Prize. Eyes on the prize is a documentary about the Civil Rights Movement. It was released on VHS and Laserdisc in 1992. The episode he was in was part nine out of fourteen episodes and it was called "Power in 1967-1968". A significant line that he spoke within the episode was,"Don't vote for me because I am a Negro, but God knows don't vote against me because I am a Negro." This line speaks to who he was a political figure for African Americans and the humbleness he exuded. His Desire for his political campaign was to vote for him because of his intelligence and humanity not for a pity vote because of his skin color.

The US Federal Courthouse Tower in downtown Cleveland, completed in 2002, was named the Carl B. Stokes Federal Court House Building. There are many other buildings, monuments and a street named for his memory within the City of Cleveland including the CMHA Carl Stokes Center, Stokes Boulevard, and the eponymous Carl Stokes Brigade club. Members of the Brigade celebrate his birthday every year at Lakeview Cemetery with gravesite services.

In November 2006, the Western Reserve Historical Society opened an exhibit entitled Carl and Louis Stokes: from Projects to Politics. Focusing on the brothers' early life at the Outhwaite projects, Service in World War II, and eventual rise to politics, the exhibit ran until September 2008.

After his election, Stokes said, "I can find no more fitting way to end this appeal, by saying to all of you, in a more serious and in the most meaningful way that I can, that truly never before have I ever known to the extent that I know tonight, the full meaning of the words, ‘God Bless America', thanks a lot."