Hamill has gained a reputation as a prolific voice actor. He first did voice acting work in the early 1970s voicing the character Corey Anders on the Saturday morning cartoon Jeannie by Hanna-Barbera Productions. He later played Sean in the Ralph Bakshi film Wizards, which was released just three months before Star Wars in 1977.

On January 11, 1977, before shooting one of his scenes in Star Wars, Hamill was in a car accident in which he fractured his nose and left cheekbone, requiring seven hours of surgery. As a result, a double was used for the landspeeder pickup shots. According to Hamill in a recorded interview, he was driving his BMW on a freeway, became distracted, and seeing that he was missing his offramp, attempted to negotiate four lanes of traffic. Some real scars from the crash appear on Luke's face in The Empire Strikes Back. Hamill later said that the stories surrounding his injuries had become exaggerated. Confirming that he had only broken his nose, Hamill observed that "over the years it's [been] built up into having my face reconstructed with plastic surgery."

On December 17, 1978, Hamill married dental hygienist Marilou York in a private civil ceremony. They have three children together: Nathan (born 1979), Griffin (born 1983), and Chelsea Elizabeth (born 1988). He also has one grandchild by his son Nathan. Nathan was born during the production of The Empire Strikes Back and had a cameo appearance as one of the Royal Guards of Naboo in Star Wars: Episode I – The Phantom Menace. Chelsea made a photographic appearance as an infant Axel Walker in the 1990 television series The Flash; the same photograph was used in the 2014 series.

Notable video game voice roles include Detective Mosely in Gabriel Knight: Sins of the Fathers and Gabriel Knight 3: Blood of the Sacred, Blood of the Damned, Assistant Director Wilson in Soldier of Fortune II: Double Helix, Adrian Ripburger in the LucasArts game Full Throttle, two installments of Crash Bandicoot series, Wolverine in X2: Wolverine's Revenge, which was the tie-in game to the film X2, Goro Majima in Yakuza, Malefor The Dark Master in The Legend of Spyro: Dawn of the Dragon, The Watcher in Darksiders, and Master Eraqus in Kingdom Hearts Birth by Sleep. The creator of Kingdom Hearts, Tetsuya Nomura, is a big fan of all of Hamill's work. There is also another character, Master Xehanort, who was voiced by Leonard Nimoy, the actor of Spock. Tetsuya Nomura stated that they wanted the two for the roles, as the two characters are rivals, referencing the rivalry between fans of Star Wars and fans of Star Trek. He also narrated Call of Duty 2: Big Red One, the title being a reference to the 1980 war film he starred in.

According to a 1981 profile in People magazine, Hamill's "first serious love" was an offscreen relationship he engaged with, with co-actor Anne Wyndham, cast as his sister on General Hospital. Hamill would later describe experiencing seasons of on-set tension, having to work together, after their relationship ended. In a 2017 interview, Hamill attributed his long happy marriage to a non-actor, to learning, through his relationship with Wyndham, the danger of being competitive when in a relationship with a fellow actor.

Hamill voiced the character of Todd Wainio in World War Z, a critically acclaimed audiobook based on Max Brooks' novel of the same name. He also provided the entire cast of voices for a 1983 audiobook version of Pinocchio with unique characteristics for each. Hamill also reads life into the characters of the popular Juvenile fiction book series, The Spiderwick Chronicles Volumes I–III, by Holly Black and Tony DiTerlizzi.

He guest starred in The Simpsons episode "Mayored to the Mob" as himself. On the audio commentary of the episode, he says that he has been a fan of the show since it debuted in 1987 on The Tracy Ullman Show and that it was a personal thrill to work with Dan Castellaneta, the voice of Homer Simpson. He has also guest starred in Family Guy and was also a recurring voice actor on Seth Green's Robot Chicken. He has also played himself in two episodes of the Disney Channel animated series Pepper Ann.

Hamill returned to film after a six-year hiatus with the 1989 science fiction film Slipstream. He continued to star in films throughout the 1990s, including in such films as the thriller Midnight Ride, The Guyver in 1991, the 1995 remake of Village of the Damned, and the 1998 Swedish action film Hamilton. Hamill appeared in the 2001 film Jay and Silent Bob Strike Back as the supervillain Cocknocker, a role which parodies both himself and roles he has played in the past.

Hamill was the voice of The Hobgoblin in the 1990s Spider-Man animated series, and his other Marvel superhero genre roles include the Gargoyle in the animated series of The Incredible Hulk, Maximus in Fantastic Four, Klaw in Avengers: Earth's Mightiest Heroes and multiple characters in Ultimate Spider-Man. Hamill voiced Solomon Grundy and Trickster in the DC animated universe series Justice League and Justice League Unlimited, the murderous gangster Tony Zucco in The Batman, an animated series unrelated to the various DC animated universe series. He voiced Spectre in an episode of Batman: The Brave and the Bold.

Hamill's role as the Joker began in the 1992 series Batman: The Animated Series and continued to many later spin-off series, video games and films. Hamill received critical acclaim for his performance, which put him in high demand as a voice over actor of cartoon villains.

Hamill also voiced Joker in three episodes of Superman: The Animated Series, five episodes of The New Batman Adventures, five episodes of Justice League, an episode of Static Shock and a few segments in Robot Chicken. He also voiced the Joker in the 1993 theatrical film Batman: Mask of the Phantasm and the 2000 direct-to-video film Batman Beyond: Return of the Joker.

Hamill is credited as the narrator in Ancient Voices, a 1999 series of documentaries on archaeology and ancient history produced by as a BBC/The Learning Channel co-production, and published by Time-Life as a DVD series. He also narrated the Medal of Honor and Silver Star citations of Tibor Rubin, Ralph E. Pomeroy, John Finnigan and Mitchell Red Cloud Jr. for the 2013 Korean War documentary Finnigan's War directed by Conor Timmis.

In 2003, Hamill starred in the two-hander play Six Dance Lessons in Six Weeks as the acerbic dance instructor Michael Minetti. He played opposite Rue McClanahan for the season at the Coconut Grove Playhouse in Miami, and opposite Polly Bergen as the production moved on to Broadway.

Hamill also directed and starred in the 2004 direct-to-DVD Comic Book: The Movie. A comic book fan who attended science fiction and comic conventions before he became famous, Hamill stated that his character was based on an exaggerated version of himself. He and his crew shot most of the "mockumentary" film during the 2002 San Diego Comic-Con and enlisted Stan Lee, Kevin Smith, Bruce Campbell and Hugh Hefner in small roles. The movie won an award for Best Live-Action DVD Premiere Movie at the 2005 DVD Exclusive Awards.

Hamill voiced the Joker alongside his Batman: The Animated Series co-star Kevin Conroy as Batman and Jason Hillhouse as Dick Grayson in a feature of a storyboard scene included in the 2005 Special Edition DVD of Tim Burton's 1989 film Batman. This scene depicted the origin of Robin, which was not filmed because the producers felt it was out-of-place with the rest of the film.

During a 2011 Comic-Con, when asked about Heath Ledger's Oscar-winning portrayal of the character in Christopher Nolan's The Dark Knight, Hamill claims it was the most original performance he has ever seen since Anthony Hopkins' Oscar-winning portrayal of Hannibal Lecter in The Silence of the Lambs.

Hamill is an outspoken member of the Democratic Party. Prior to the 2012 election for the presidency of the United States, Hamill referred to Mitt Romney as a "snake oil salesman". In 2016, he endorsed P.G. Sittenfeld's candidacy in the 2016 election for the United States Senate. He has also criticized the tweets of Donald Trump by reading them out in his Joker voice.

Initially, both Disney and Hamill were coy about whether Hamill would be a cast member of The Force Awakens. In September 2013, Robert Englund, actor and long-time friend of Hamill, said that Hamill was currently working out in the gym. Englund stated "Mark now – they've got Mark in the gym because Mark's coming back as Luke Skywalker. They've got him doing his sit-ups." It was previously reported that both Hamill and Fisher had been assigned nutritionists and personal trainers to work with ahead of production.

Hamill returned to the Star Wars universe in 2014, when he voiced the ancient Sith Lord Darth Bane, in the final episode of the animated series The Clone Wars. He was nominated for a Daytime Emmy Award for his performance.

Hamill has commented that if there would ever be an animated version of Batman: The Killing Joke, he would gladly voice the Joker again, encouraging fans to campaign for said adaptation. On July 17, 2015, Hamill tweeted that he had his fingers crossed in hopes that he would be contacted to reprise his role as the Joker in the animated adaptation. On July 27, Collider reported that Hamill will voice the Joker in the film. The film was released in theaters for a two-day limited time. It was released on Digital HD on July 27, 2016. It was released on DVD and Blu-Ray on August 2. Positive reception was met for Mark Hamill's performance as the Joker, with some citing it as his best performance of the character.

Hamill is a lifelong fan of Laurel and Hardy. In June 2016, he called into The Ross Owen Show on Black Sky Radio to talk for over an hour about his passion for Stan and Ollie. He was also an early fan of David Letterman, having occasionally appeared on Late Night with David Letterman, as well as taping every episode and keeping a journal documenting the show. After encountering Writer Chris Elliott, Hamill was asked for assistance in helping determine the 1,000th Viewer Mail that Letterman had answered. His practice continued to Letterman's new show on CBS, but eventually stopped.

He became a supporter of English football club Wolverhampton Wanderers F.C. in 2017.

He stars in the 2018 film Con Man, an independent film about the life of Barry Minkow, the famous con man. Hamill plays Minkow's father, Robert Minkow.