Cryer’s first professional acting effort was as David in the Broadway play Torch Song Trilogy, replacing Matthew Broderick, whom he “closely resembled.” He reprised the role in San Francisco and Los Angeles. Cryer was later a standby and replacement for Broderick in the role of Eugene Jerome in the original Broadway production of Neil Simon’s Brighton Beach Memoirs in 1984.

At age 19, Cryer appeared in the 1984 romantic comedy film No Small Affair, in the lead role as Charles Cummings, after the original production with Matthew Broderick was shut down due to a heart attack by director Martin Ritt. He went on to have small roles in films and television movies.

Cryer then starred in the 1987 film Hiding Out as a 29-yr old stockbroker on the run from a Mafia hit man. His mother Gretchen played his aunt. The film broke even, but Cryer’s performance as a much-older character was critically acclaimed.

In 1989, he got the lead role in the TV comedy series The Famous Teddy Z. His performance gained poor reviews and the show was canceled after the first season.

In 1990 Cryer appeared as Sandy in an Off-Broadway adaptation of Carnal Knowledge. That same year he starred with Charlie Sheen in the Jim Abrahams comedy Hot Shots!, which was received very positively. Cryer is frequently linked to the Brat Pack. In a March 2009 interview on Anytime with Bob Kushell, Cryer stated that he had auditioned for St. Elmo’s Fire but was not cast in a role. In 1993, he was asked to audition for the role of Chandler Bing on Friends, while doing a play in London. His reading was videotaped by a British casting agent but the tape failed to arrive in the U.S. before the network had made its final decision.

In 1995, he was cast as Bob in the sitcom Partners, which, like his prior show The Famous Teddy Z, was canceled after its first season. In an interview with Time Out New York he stated, “Hey, every show I’m in goes down. Think about this: George Clooney was in 28 pilots, or something. It means nothing.” After guest starring on shows such as Dharma & Greg and The Outer Limits, he successfully wrote and produced the film, Went to Coney Island on a Mission from God… Be Back by Five. It debuted in 1998 at the Los Angeles Film Festival and gained positive reviews from critics. Leonard Maltin from Playboy Magazine called it “a breath of fresh air.” That same year, Cryer landed in another TV series, the Fox sitcom Getting Personal, alongside Vivica A. Fox and Duane Martin. Although the show was picked up for a second season after its abbreviated spring run, it was canceled that fall, after airing 17 episodes in total.

In 1999, Cryer appeared as Neal in Jeffrey Sweet’s play Bluff at the Victory Gardens Theater. In 2000, he was cast as the lead in a comedy series called The Trouble With Normal. For the third time, Cryer starred in a show which was canceled after its first season.

Cryer married British actress Sarah Trigger in 1999, with whom he has a son, Charlie Austin. In 2004, the couple divorced. On a February 2007 episode of The Tonight Show with Jay Leno, he announced that he would marry entertainment reporter Lisa Joyner; the couple married in Mexico in June 2007. On September 29, 2009, Cryer and Joyner announced that they adopted a baby girl.

Cryer’s long run of unsuccessful TV projects finally ended in 2003. Against the wishes of CBS executives (who were aware of his past failures) and due to a friendship with Charlie Sheen, he was cast as Alan Harper on the hit comedy series Two and a Half Men. He has earned seven Primetime Emmy Award nominations and two wins for his acting work on the show. In a comment on the show’s high ratings, he said: “When you’re on a show that’s fighting for survival every week, you stop trusting your instincts, because you think, ‘My instincts haven’t worked so far.’ But when people clearly like the show and are watching it in great numbers, it takes a huge amount of pressure off you. It allows you to trust your instincts and go with what has worked for you before.” After former co-star Charlie Sheen’s departure from the series, Cryer’s character became the show’s main protagonist (with Ashton Kutcher being cast as the co-lead) throughout the final four seasons, mainly due to the show’s retooled plot. At the end of the series of Two and a Half Men, Cryer is the only actor to have appeared in every episode of the series; Sheen was fired in March 2011 and Cryer’s on-screen son Angus T. Jones left the series at the end of season 10, after describing the show as “filth” and calling himself a “paid hypocrite.” All appeared to be forgiven later, as Jones, unlike Charlie Sheen, appeared to great applause in the finale. Before being cast for Two and a Half Men, Cryer auditioned for the role of Gaius Baltar on the Sci-Fi Channel’s reimagined Battlestar Galactica, but the role went to James Callis. In 2008, Cryer appeared with Laurence Fishburne and James Cromwell in the film Tortured, and in 2009 co-starred with James Spader in the film Shorts.

Cryer currently appears in the highly popular CBS drama series NCIS, where he currently plays Navy Dr. Cyril Taft who treats NCIS Special Agent Leroy Jethro Gibbs (Mark Harmon). Cryer had expressed a desire to appear in NCIS since it premiered on September 23, 2003.

In 2011, Cryer played the role of David in a concert staging of Stephen Sondheim’s musical Company with the New York Philharmonic at Lincoln Center. The all-star cast was headed by Neil Patrick Harris and Patti LuPone. The concert subsequently aired on PBS’s Great Performances.

When Pretty in Pink co-star Molly Ringwald told Out magazine in 2012 that she believed Cryer’s character was gay, Cryer rebuffed the claims and said he has had to live with others’ “faulty” gaydar. Also in 2012, Joyner told Jeff Probst that when she and Cryer started dating, she wondered if he might be gay because “he never kissed me.” Cryer was asked in 2014 if he was “mistaken for gay”; he called himself “an effeminate heterosexual dork” and made a tongue-in-cheek remark about never being propositioned: “Fellas, you’re dropping the ball.”

In 2015, Cryer released a book titled So That Happened, a breezy, often comic tale chronicling Cryer’s 30-year career on stage, film and television.

On May 21, 2018, Cryer was featured in the premier of Episode 1, Season 9 of genealogy program Who Do You Think You Are? Cryer’s journey took him from America to Scotland as he uncovered the dramatic tale of his ancestor James Adams, a Scottish Covenanter soldier who was captured during the Battle of Dunbar in 1650, and endured horrific conditions as a prisoner. He was then transported to America an indentured servant to work at the Saugus Iron Works at Lynn, Massachusetts. As part of his research for the episode, Cryer visited the site of the Battle of Dunbar, Durham Cathedral in Durham, North East England – where surviving Scottish prisoners were held until they were indentured – and the Saugus Iron Works national historic site. Cryer said: “Seeing the resilience of my family over centuries, you can see the legacy he left. I can’t help but feel lucky…clearly, the resilience of my family, that spine of steel, was not something that came from nowhere. Moving forward, I’m going to take James Adams’ strength as my inspiration and know that when you go through very, very difficult times, if you can turn around and help the people around you who had it even worse, that’s real strength. And I aspire to be one of those people.”

On November 16, 2018, it was announced that Cryer had been cast as Lex Luthor on The CW’s Supergirl in a recurring role, starting in the fifteenth episode of Season 4, titled “O Brother, Where Art Thou?”. He is set reprise the role in the Batwoman and The Flash episodes of the Arrowverse crossover Crisis on Infinite Earths.

On April 15, 2019, Cryer joined other WGA writers in firing their agents as part of the WGA’s stand against the ATA and the unfair practice of packaging.