In 1976, Duffy landed the role of Mark Harris in the short-lived television series Man from Atlantis. Following the series' cancellation in early 1978, he got his big break in the role of Bobby Ewing on the TV series Dallas. The show became a worldwide phenomenon, ranking in the top 3 for the first half of the 1980s. Despite its success, Duffy opted to leave the series in 1985 with his character being killed off onscreen. However, with both the show and his career on the decline, he returned in 1986 in the infamous shower scene that rendered the entire 1985–1986 season "just a dream". Duffy then remained with the series until its cancellation in 1991. He also appeared in several episodes of the spin-off series Knots Landing between 1979-82. Throughout the 13-year run of Dallas, Duffy directed several episodes of the series. In 1992, he began a role of the public announcing host and Pete's rival, Harold Hatchback (which is from Rob Paulsen's voice role) in the episode, "Buddy Building" from Goof Troop.
At the end of Dallas' run in 1991, Duffy began another popular television role, as Frank Lambert on the family sitcom, Step by Step in which he co-starred with Suzanne Somers. The series ran until 1998, and Duffy also directed 49 episodes. Also in the 1990s, he appeared in two Dallas reunion TV movies; J.R. Returns (1996) and War of the Ewings (1998), both of which he also co-produced. In an interview on the UK's Mrs. Merton chat show in 1997, Duffy stated that he and Dallas co-star Larry Hagman were planning a third Dallas TV movie, but this project failed to materialize. He has reunited on several occasions with many of his Dallas co-stars both onscreen and off, most notably for the non-fiction television special Dallas Reunion: Return to Southfork in 2004.
Duffy continued to act in the occasional guest or voice acting appearance, including the shows Family Guy (in which he appeared in a live action scene with Victoria Principal as they spoofed the Dallas shower scene), as well as Justice League and Touched by an Angel.
More recently, Duffy starred in television movies Falling in Love With the Girl Next Door and Desolation Canyon. In 2006, he began a limited run on the daytime soap The Bold and the Beautiful as Stephen Logan, returning to the role every now and then. From April - July 2008, he also hosted Bingo America, a partially interactive game show on GSN.
Duffy has also tried his hand at singing and in 1983 he had a hit in Europe with "Together We're Strong", a duet with French female singer Mireille Mathieu. The single reached number 5 in The Netherlands in April 1983.
In 2010, Duffy began appearing as a paid spokesperson for "Miracle Ear" hearing aids.
In 2010, Duffy narrated the ESPN 30-for-30 documentary entitled "Pony Excess", which profiled the SMU football scandal of the 1980s. Coincidentally, SMU is located in Dallas.