Starting with Uncaged, Morgan has appeared in over 25 feature films. However, the bulk of his work has been in television. He was a major character in the 1996–97 television series The Burning Zone, appearing in eleven of its nineteen episodes. In 2005 and 2006, Morgan simultaneously appeared in three television series: in the CW series Supernatural as John Winchester, in a recurring role on ABC's Grey's Anatomy as heart transplant patient Denny Duquette, and as Judah Botwin in two episodes of the Showtime series Weeds. He has also guest-starred in a number of television series, including ER; JAG; Walker, Texas Ranger; Angel; '; Sliders; The O.C.; and Monk. In 2007, Morgan was cast in a proposed project by Grey's Anatomy creator Shonda Rhimes. The series, tentatively titled "Correspondents", was to have started production in summer 2007. ABC instead picked up a spin-off of Grey's Anatomy, called Private Practice, that was also created by Rhimes. As a result, "Correspondents" was shelved. In 2007, Morgan starred in the film The Accidental Husband, which finished filming in March 2007 and was released on DVD in 2009. Morgan starred in the thriller The Resident in 2011 along with his P.S I Love You co- star Hilary Swank. He also appeared in the drama film Days of Wrath in 2008. In 2009, Morgan portrayed The Comedian, a cigar-chomping antihero, in Watchmen, based on Alan Moore's graphic novel. The same year, Morgan appeared in Taking Woodstock, and played Clay in a comic book movie adaptation of The Losers. He also played Jeb Turnbull in the DC comic book movie Jonah Hex Morgan appeared in the Texas crime thriller Texas Killing Fields as a homicide detective in 2011. The following year, Morgan starred in the television drama seriesMagic City, which centered on mob life in 1950s Miami. The same year, Morgan starred in the horror thriller The Possession, and had a supporting role in the war film Red Dawn. In 2014, Morgan played Charlie Peters, the owner of the Cake House, in the season finale of Shameless. In November 2014, Morgan was cast as Joe DiMaggio opposite Kelli Garner as Marilyn Monroe in The Secret Life of Marilyn Monroe, a Lifetime four-hour miniseries based on J. Randy Taraborrelli's book of the same name. In 2015, Morgan portrayed Deaf Smith in Texas Rising, a five-part mini-series which aired on the History Channel. Also in 2015, Morgan became a regular cast member for season 2 of the CBS sci-fi drama Extant. He also appeared in an uncredited role in ', as Bruce Wayne's father, Thomas Wayne. It has long been rumored that if a movie based on the DC comics hero The Flash was made using the Flashpoint Paradox storyline, that Morgan would reprise his role as Thomas Wayne and play the alternate universe Batman in the film. In 2015, Morgan took on the role of freelance investigator Jason Crouse, opposite Julianna Margulies, in the popular CBS TV series The Good Wife, until that series' conclusion in spring 2016. That year, Morgan began his most noted role to-date, as Negan on the AMC TV series The Walking Dead. He made his first appearance in the sixth-season finale on April 3, 2016 and served as the primary antagonist of the seventh and eighth seasons. In 2015, had a lead role in Jonás Cuarón's thriller film Desierto. On May 28, 2017, Morgan drove the 2017 Chevrolet Corvette Grand Sport Pace Car to lead the starting field of the 101st Indianapolis 500. In September, Morgan appeared in a commercial for the online gameEvony. Morgan was 5th billed in the Dwayne Johnson film Rampage, released in April 2018. Morgan reprised his role as John Winchester in the thirteenth episode of the fourteenth season of Supernatural, which served as the 300th episode of the series, which aired on February 7, 2019.
Morgan was married to actress Anya Longwell from 1992 to 2003. They divorced in 2003. In 2007, he was briefly engaged to his former Weeds costar Mary Louise Parker; their engagement ended in April 2008. In 2009, Morgan began a relationship with actress Hilarie Burton. The couple's son was born in March 2010. Their daughter was born in February 2018. On October 5, 2019, the couple got married, although many erroneously speculated that they had married in 2014. Morgan and Burton made their home in the town of Rhinebeck in Dutchess County, New York on a 100-acre working farm in the Hudson Valley with cows, ducks, chickens, alpacas, donkeys, and an emu. Since 2014, they have been co-owners of Samuel's Sweet Shop, a Rhinebeck candy store they saved from being closed after the previous owner, a friend of theirs, died suddenly.