Denise Crosby began her career appearing as Lisa Davis on the soap opera Days of Our Lives. She has appeared as Dr. Gretchen Kelly in three episodes of Lois & Clark: The New Adventures of Superman, and as a sheriff on The Adventures of Brisco County, Jr. episode “No Man’s Land”. In the early 1990s, she played the role of the mayor in the short-lived series Key West. Crosby had a small recurring role in Aaron Spelling’s prime time drama, Models Inc, a spin-off from Melrose Place. She was a guest star on the eighth season of The X-Files for two episodes, in which she plays a doctor who took examinations of Agent Scully’s baby. In 1991, she was a guest star in “The Deadly Nightshade”, a first season The Flash episode as Dr. Rebecca Frost. In 2006, she was a guest star in Dexter as Dexter’s first victim. Crosby had a recurring role in Southland as Detective Dan “Sal” Salinger’s wife.

One of her very first film appearances was in the 1982 Nick Nolte/Eddie Murphy film 48 Hrs. This was followed by a small role in the 1982 film Trail of the Pink Panther, which she reprised in the immediate sequel Curse of the Pink Panther. In 1986, she played a robotics engineer, Nora Hunter, in the science fiction movie Eliminators, the leading role in the film Dolly Dearest in 1992, appeared in Stephen King’s Pet Sematary and Quentin Tarantino’s Jackie Brown. She starred in the 2002 western horror film Legend of the Phantom Rider. Crosby starred in the Tobe Hooper horror film Mortuary. She also appeared in the 1998 movie Deep Impact starring Elijah Wood.

In 1987, Crosby was cast in the role of Tasha Yar for the much publicized return of Star Trek to television in the syndicated series Star Trek: The Next Generation. She had been chosen to play Counsellor Deanna Troi before Gene Roddenberry switched the roles that she and Marina Sirtis had originally been given. Initially one of the top-billed characters and featured prominently in episodes such as “The Naked Now” and “Code of Honor”, the role of Tasha gradually moved into the background as other members of the ensemble cast became a greater focus of the series. It has been reported that Crosby grew disillusioned with her role because of its “Uhura-like” status: “I was struggling with not being able to do much with the character. I had all these ideas and couldn’t do them. I was just stage dressing.” Ultimately, Crosby decided to leave the show. Her character was killed by the alien creature Armus during the episode “Skin of Evil.” She had appeared in 22 episodes when she left.

In later years, Crosby approached the TNG production team with the idea of reprising her role of Tasha Yar. This came to be in season three’s “Yesterday’s Enterprise” in which an alternate timeline is created after the USS Enterprise-C, the predecessor to TNG’s USS Enterprise-D, comes forward 22 years in time. Yar joined the Enterprise-C before it returned to its own time. During the documentary Trekkies, Crosby commented that her Tasha Yar character had to die in order to get “the best episodes”.

Crosby has a recurring role on Showtime’s 2013 series Ray Donovan. In 2014, she was on AMC’s The Walking Dead as Mary, a member of a group of cannibals. The character first appears in the penultimate episode of Season 4, and made her final appearance in the season five premiere, “No Sanctuary”, appearing in a total of three episodes. More recently she can be seen in roles in the SyFy television series The Magicians as well as the Nathan Fillion series Castle.