In 2005, she appeared in Supernatural as Jessica Moore, Sam Winchester's doomed girlfriend who is killed by a demon in its pilot episode.

[7] In 2010, Palicki joined the FOX television drama Lone Star, which was cancelled after two episodes, despite good reviews.

[8] In 2011, Palicki portrayed Wonder Woman in a television pilot produced by David E. Kelley for NBC.

[9][10] She played the recurring role of Dr. Samantha Lake in season one of the sitcom About a Boy in 2014, reuniting with Friday Night Lights showrunner Jason Katims.

ABC ordered a pilot episode for a spin-off, Marvel's Most Wanted, featuring her character in the lead role,[19] but did not develop it as a series.

[20] In July 2016, Palicki was cast as Kelly Grayson in The Orville, a science fiction comedy-drama series created by Seth MacFarlane, who also stars in it as Captain Mercer, her character's ex-husband.

In 2016, Palicki and her brother, Eric, collaborated on writing their first comic book, titled No Angel, published by Black Mask Studios.

[24][25] In September 2014, her representative confirmed that she was engaged to stuntman Jackson Spidell, whom she met on the set of John Wick.