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Shatner was an occasional celebrity guest on The $20,000 Pyramid in the 1970s, once appearing opposite Nimoy in a matchup billed as "Kirk vs. Spock". His appearances became far less frequent after a 1977 appearance, in which, after giving an illegal clue at the top of the pyramid ($200) which deprived the contestant of a big money win, he threw his chair out of the Winner's Circle.

He appeared on the Match Game, though he was never a regular on this program.

Shatner had a long dry spell in the decade between the original Star Trek series and the first Trek film, which he believes was due to his being typecast as Captain Kirk, making it difficult to find other work. Moreover, his wife Gloria Rand left him. With very little money and acting prospects, he lived in a truck bed camper in the San Fernando Valley until acting bit-parts turned into higher paying roles.  Shatner refers to this part of his life as "that period," a humbling one in which he would take any odd job, including small party appearances, to support his family. Perhaps the nadir was his role in Big Bad Mama, prized by Shatnerites for his nude scene with Angie Dickinson. He did however land a starring role in the western-themed secret agent series Barbary Coast during 1975 and 1976, as well as a major role in the horror film The Devil's Rain. He also made guest appearances on many 1970s television series such as The Six Million Dollar Man, Columbo, The Rookies, and Mission: Impossible.  The dry spell ended for Shatner (and the other Star Trek cast members) when Paramount produced Star Trek: The Motion Picture in 1979, under pressure from loyal fans of the series. Its success re-established Shatner as an actor, and Captain Kirk — now promoted to Admiral — as a cult icon.

While continuing to film the successful series of Star Trek movies, he returned to television in the 1980s, starring as a police officer in the T.J. Hooker series from 1982 to 1986. He then hosted the popular dramatic reenactment series Rescue 911 from 1989 to 1996. During the 1980s, Shatner also began dabbling in film and television directing, directing numerous episodes of T.J. Hooker and the feature film Star Trek V: The Final Frontier.

As the unwilling central figure of a widespread geek-culture of Trekkies, Shatner is often humorously critical of the sometimes "annoying" fans of Star Trek. He also has found an outlet in spoofing the cavalier, almost superhuman character persona of Captain Kirk, in films such as Airplane II: The Sequel (1982), National Lampoon's Loaded Weapon (1993) and Saturday Night Live, in which he advised Star Trek fans to "Get a life", repeating a popular catch-phrase. Shatner also appeared in the film Free Enterprise in 1998, in which he played himself and tried to dispel the Kirk image of himself from the view of the film's two lead characters.

Shatner has enjoyed success with a series of science fiction novels published under his name, though most were written by uncredited co-writers like Ron Goulart. The first — published in 1990 — was TekWar. This popular series of books led to a Marvel Comics series, to a number of television movies, in which Shatner played a role, and to a short-lived television series in which Shatner made several appearances; he also directed some episodes. In 1995, a first-person shooter game named William Shatner's TekWar was released, and was the first game to use the Build engine.

In the 1990s, Shatner appeared in several plays on National Public Radio, written and directed by Norman Corwin. Shatner was cast as "The Big Giant Head," a womanizing party-animal and high-ranking officer from the same alien planet as the show's protagonists in several episodes of the television series 3rd Rock from the Sun. The role earned Shatner a nomination for an Emmy. In 2003, Shatner appeared in Brad Paisley's Celebrity country music video along with Little Jimmy Dickens, Jason Alexander, and Trista Rehn.

In 2004, Shatner was cast as the eccentric but highly capable attorney Denny Crane for the final season of the legal drama The Practice, for which he was awarded an Emmy, and then its subsequent spin-off, Boston Legal, for which he won a Golden Globe, an Emmy in 2005 and nominated again in 2006.  With the 2005 Emmy win, Shatner became one of the few actors along with co-star James Spader as Alan Shore, to win an Emmy award while playing the same character in two different series.  Even rarer, Shatner and Spader each won a second consecutive Emmy while playing the same character in two different series.

Also in 2004, Shatner became a "Celebrity Photographer" for Playboy's Cyber Club.

In 2005, Shatner executive-produced and starred in the Spike TV reality miniseries Invasion Iowa. On October 19, 2005, while working on the set of Boston Legal, Shatner was taken to the emergency room for lower back pain.  He eventually passed a kidney stone, but recovered and soon returned to work.

In 2006 Shatner sold his kidney stone for US$75,000 to GoldenPalace.com. In an appearance on The View on Tuesday, May 16, 2006, Shatner said  US$75,000, with an additional US$20,000 raised from the cast and crew of Boston Legal, paid for the building of a house by Habitat for Humanity.

Shatner also plays on the World Poker Tour in the Hollywood Home games.  He plays for the Wells Fargo Hollywood Charity Horse Show. Shatner has appeared in priceline.com commercials both online and on TV, as the "Chief Negotiating Officer." Shatner is also the CEO of the Toronto, Ontario-based C.O.R.E. Digital Pictures, which provided the special effects for the 1996 film Fly Away Home.

On August 20, 2006, Shatner was featured on Comedy Central's Roast of William Shatner. Jason Alexander acted as roastmaster with  (in alphabetical order) Andy Dick, Farrah Fawcett, Greg Giraldo, Lisa Lampanelli, Artie Lange, Nichelle Nichols, Patton Oswalt, Kevin Pollak, Jeffrey Ross, George Takei, Betty White, and Fred Willard performing the roasting duties. Special, pre-taped, guest appearances were made by Leonard Nimoy, Sandra Bullock, Ben Stiller, Sarah Silverman, Jimmy Kimmel, and Clint Howard.

In October 2006, Shatner accepted to host the new ABC game show Show Me the Money, which began in November 2006. The show was cancelled in December 2006 due to low ratings. It was Shatner's first unsuccessful attempt at a series since Barbary Coast in 1976. Shatner continues to co-star on Boston Legal. On March 22, 2007, Shatner was announced as the inductor of legendary professional wrestler/broadcaster Jerry "The King" Lawler at the 2007 WWE Hall of Fame induction ceremony, set to occur on March 31, 2007 at the Fox Theater in Detroit, Michigan. Shatner was chosen because of a memorable 1995 appearance on WWF Monday Night Raw  in which Shatner, promoting the TekWar TV series, pushed Lawler to the ring canvas during an interview segment. Shatner later managed fellow Canadian Bret "Hit Man" Hart in a match against Jeff Jarrett, managed by Lawler. Shatner briefly reprised his role as James T. Kirk for a recent 2006 DirecTV advertisement featuring footage from Star Trek VI. Shatner has starred in a series of Kellogg's All-Bran cereal commercials in the UK and Canada.

In January 2007, Shatner launched a series of daily vlogs on his life called ShatnerVision on the LiveUniverse.com website.  Along with his daughter Lisabeth; they provide a unique and unparalleled look into Shatner's private life and adventures in life.

Shatner also appeared in the ABC reality television series Fast Cars and Superstars: The Gillette Young Guns Celebrity Race, featuring a dozen celebrities in a stock car racing competition.  In the first round of competition, Shatner matched up against former NFL coach Bill Cowher and former volleyball superstar Gabrielle Reece.  Shatner was disqualified in the episode for repeatedly crossing a safety line on the track.  As of 2007, Shatner is the first Canadian actor to star in three successful TV series on 3 different networks (NBC, CBS and ABC).

Shatner has a Star on the Hollywood Walk of Fame (for Television work) at 6901 Hollywood Blvd. He also has a star on the Canadian Walk of Fame.

On November 20, 2007 William Shatner was featured as part of the "What's Your Game?" national television commercial series for World of Warcraft along with Mr T. and Verne Troyer.