2005–present: Return to television and independent films
In 2005–06, she played the recurring role of Ellie Harp, the biological mother of Peyton Sawyer (played by Hilarie Burton), who battles breast cancer, on the third season of the WB Network series One Tree Hill.
In 2007 and 2008, Lee appeared on the ABC dramedy Dirty Sexy Money as Andrea Smithson, the mother of Brian Darling's (Glenn Fitzgerald) illegitimate child. Lee, along with several other Twin Peaks cast members, guest starred in a special Twin Peaks-themed episode of Psych titled "Dual Spires." Other cast members reunited with Lee included Sherilyn Fenn (Audrey Horne), Dana Ashbrook (Bobby Briggs), Ray Wise (Leland Palmer), Lenny Von Dohlen (Harold Smith), Robyn Lively (Lana Budding Milford), and Catherine E. Coulson (The Log Lady).
In 2010, she appeared in a supporting role as April in Debra Granik's Winter's Bone (which won best picture at the Sundance Film Festival in 2010). The film is about a seventeen-year-old girl (Jennifer Lawrence) in the rural Ozarks, caring for her mentally-ill mother and her younger brother and sister, when she discovers that her father put their house and land up as a bond for a court appearance, at which he failed to appear. Lee won two Awards for Best Ensemble at Detroit Film Critics Society and Gotham Awards, shared with the cast. Lee played Lucie Sliger in the 2011 crime thriller Texas Killing Fields alongside Jessica Chastain, Sam Worthington and Chloë Grace Moretz.
In the art drama thriller White Bird in a Blizzard (2014), written and directed by Gregg Araki, she played May opposite Shailene Woodley and Eva Green. In 2015, at the Twin Peaks UK Festival, Lee confirmed that she would be returning to Twin Peaks for the 2017 limited Showtime run.
In 2016, she appeared in a supporting role as Air in the Netflix production Rebirth, which premiered at the Tribeca Film Festival, and had a small part as Karen in Café Society, written and directed by Woody Allen. The film had its premiere at the 2016 Cannes Film Festival. In 2017, she reprised her role as Laura Palmer in Twin Peaks and also playing the part of Carrie Page, making it her third character in the series. Although she was credited in every one of the 18 episodes, most of her appearance was in archive footage. New material of her was seen in the episodes Part 2, Part 17 and Part 18. The same year, she starred as Alley in the short film Dead Ink Archive by David Schendel, making it their second collaboration after the 1994 film The Can (which was filmed in the late 1980s). In 2018, Lee played one of the leads in the Teen-Thriller Deadly Scholars (also known as #SquadGoals) as Emily Hodges.
In 2019, Lee returned to Theater, playing alongside Judd Nelson in Love Letters. She performed the play before in 1991 with Luke Perry and Tim Daly as co-stars.
The 2020-released book Laura's Ghost: Women Speak about Twin Peaks by Courtenay Stallings, which explores the legacy of the fictional character Laura Palmer, played by Lee in the television show Twin Peaks, features interviews and a foreword from Lee.