Cosby met his wife Camille Hanks while he was performing stand-up in Washington, D.C., in the early 1960s, and she was a student at the University of Maryland. They married on January 25, 1964, and had five children: Daughters Erika Ranee, Erinn Chalene, Ensa Camille, and Evin Harrah, and son Ennis William. His son Ennis was shot to death while changing a flat tire on the side of a Los Angeles freeway on January 16, 1997.

In early 1997, a 22-year-old woman, Autumn Jackson, demanded $40 million from Cosby, claiming he was her biological father. He admitted to having a one-time affair with Jackson's mother and had provided money to the family until Jackson turned 18, though he disputed the paternity claim from the start. She was found guilty of extortion and sentenced to 26 months in prison; two accomplices were sentenced to five years and three months. The convictions were overturned in June 1999, on a technicality. The case was retried later, and the convictions were returned.

Cosby is an active alumni supporter of his alma mater, Temple University, and in particular their men's basketball team, whose games Cosby frequently attends (particularly during the team's glory days under coach John Chaney, who is a close friend of Cosby).

Cosby is also a Philadelphia Eagles fan. Recently, when both the Eagles' starting and backup quarterbacks were injured, Cosby sent some of his old football gear to head coach Andy Reid, joking he was ready to play if needed. He attends many public events, such as the 100th Millrose Games at Madison Square Garden in New York on February 2, 2007. He enjoys cigars, a hobby he picked up from Groucho Marx, one of his comedy influences.

Cosby is also a noted pen collector, and often frequents several well-known fountain pen stores; he is the spokesperson for Fountain Pen Hospital. He maintains homes in Shelburne, Massachusetts, and Cheltenham, Pennsylvania.

In 1965, Cosby achieved a first for African-Americans when he co-starred with Robert Culp in I Spy, an adventure show in the James Bond-style. Cosby's presence as the first black star of a dramatic television series made I Spy unique; Cosby and NBC executives were concerned that some affiliates might be unwilling to carry the series. At the beginning of the 1965 season, however, only four stations—in Georgia, Florida, and Alabama—declined the show. The rest of the country was taken with the show's exotic locales and the authentic chemistry of the stars, and it became one of the ratings hits of that television season. I Spy finished among the twenty most-watched shows that year, and Cosby was honored with an Emmy award for outstanding actor in a dramatic series, as he would be again for the next two consecutive years. Although ostensibly focused on Culp's character, the show had clearly become a vehicle for his co-star.

Throughout the series' three-year run Cosby was repeatedly confronted with the question of race. For him it was enough that I Spy portrayed two men who worked as equals despite their different races; however, critics took the show to task for not having a black character engage the racial issues that inflamed the country at that time. Cosby was relieved when the series ended, enabling him to concentrate on his family and to return to live performing.

After I Spy, he still pursued a variety of television projects: As a regular guest host on The Tonight Show and the star of an annual special for NBC. He returned with another series in 1969, The Bill Cosby Show, a situational comedy that ran for two seasons. Cosby played a physical education teacher at a Los Angeles high school (he had actually majored in physical education at Temple University); while only a modest critical success, the show was a ratings hit, finishing eleventh in its first season.

After The Bill Cosby Show left the air, he returned to his education, actively pursuing an advanced degree in education from the University of Massachusetts. This professional interest led to his involvement in the PBS series, The Electric Company, for which he recorded several segments in which he taught reading skills to younger children. In 1972, he was back in prime time with a variety series, The New Bill Cosby Show, but this time he met with poor ratings, and the show lasted only a season. More successful was a Saturday morning show, Fat Albert and the Cosby Kids, hosted by Cosby and based on his own childhood, running from 1972 to 1979, then from 1979 to 1984 as The New Fat Albert and the Cosby Kids. Some schools used the program as a teaching tool, and Cosby himself wrote his thesis on it in order to obtain his doctorate in Education in 1977.

Also during the 1970s, Cosby and other African-American actors, including Sidney Poitier, joined forces to make some successful comedy films which countered the violent "blaxploitation" films of the era. Uptown Saturday Night (1974)  and Let's Do It Again (1975) were generally praised, but much of Cosby's film work had fallen flat. Mother, Jugs & Speed (1976) costarring Raquel Welch and Harvey Keitel; A Piece of the Action, with Poitier; and California Suite, a compilation of four Neil Simon plays; were all panned. In addition, Cos (1976) an hour-long variety show on TV featuring puppets, sketches, and musical numbers, was canceled within the year. Cosby was also a regular on children's public television programs starting in the 70s, hosting the "Picture Pages" segments which lasted into the early 80s.

Cosby's greatest television success came in 1984, with the debut of The Cosby Show. For Cosby the new situation comedy was a response to the increasingly violent fare the networks usually offered. He insisted on and received total creative control of the series, and he was involved in every aspect of the series. Not surprisingly, the show had parallels to Cosby's actual family life: Like the characters Cliff and Claire Huxtable, Cosby and his wife Camille were college educated, financially successful, and had five children. Essentially a throwback to the wholesome family situation comedy, The Cosby Show was unprecedented in its portrayal of an intelligent, affluent, nonstereotypical African-American family.

Much of the material from the pilot and first season of The Cosby Show was taken from his then popular video Bill Cosby: Himself, released in 1983. The series was an immediate success, debuting near the top of the ratings and staying there for most of its long run. The familiar question of relevance came up again but was more or less drowned out by praise for the series. People magazine called the show "revolutionary," and Newsday concurred that it was a "real breakthrough."

In 1987, Cosby attempted to return to the big screen with the spy spoof, Leonard Part 6. Unfortunately, although Cosby himself was producer and wrote the story, he realized during production that the film was not going to be what he wanted and publicly denounced it, warning audiences to "stay away."

After The Cosby Show went off the air in 1992, he embarked on a number of other projects, including a notably scripted revival of the classic Groucho Marx game show You Bet Your Life (1992-1993) along with the ill-fated TV-movie I Spy Returns (1994) and The Cosby Mysteries (1994). In the mid-1990s, he appeared as a detective in black and white film noir-themed commercials for Turner Classic Movies. He also made appearances in three more films, Ghost Dad (1990), The Meteor Man (1993), and Jack (1996); in addition to being interviewed in Spike Lee's 4 Little Girls (1997), a documentary about the 16th Street Baptist Church bombing of a Birmingham, Alabama, church in 1963. Also in 1996, he started up a new show for CBS, Cosby, again co-starring Phylicia Rashād, his onscreen wife on The Cosby Show. Cosby co-produced the show that was based on a cynical British program called One Foot in the Grave, but Cosby lightened the humor. It centered on Cosby as Hilton Lucas, an iconoclastic senior citizen who tries to find a new job after being "downsized," and in the meantime, gets on his wife's nerves. Madeline Kahn costarred as Rashād's goofy business partner. Cosby was hired by CBS to be the official "spokesman" for the WWJ-TV during an advertising campaign from 1995-1998. In addition, Cosby in 1998 became the host of Kids Say the Darndest Things. After four solid seasons, Kids Say the Darndest Things was canceled. The last episode aired April 28, 2000. Cosby continued to work with CBS through a development deal and other projects.

His wellspring of creativity became manifest again with a series for preschoolers, Little Bill, which made its debut on Nickelodeon in 1999. The network renewed the popular program in November 2000. In 2001, at an age when many give serious consideration to retirement, Cosby's agenda included the publication of a new book, as well as delivering the commencement addresses at Morris Brown College and at Ohio State University. Also that year, he signed a deal with 20th Century Fox to develop a live-action feature film centering on the popular Fat Albert character from his 1970s cartoon series. Fat Albert was released in theaters in December 2004. In May 2007, he spoke at the Commencement of High Point University.