In the late 1990s, Dunst transitioned to leading roles in a number of teen films, including the satirical political comedy Dick, and the Sofia Coppola-directed drama The Virgin Suicides (both released in 1999), followed by the comedy Bring It On (2000), and the drama Crazy/Beautiful (2001). She subsequently portrayed Marion Davies in Peter Bogdanovich's period drama The Cat's Meow (2001). Dunst soon gained a resurgence of mainstream attention for her role as Mary Jane Watson in Sam Raimi's Spider-Man (2002), a role which she reprised in the sequels Spider-Man 2 (2004) and Spider-Man 3 (2007). She had a minor part in the psychological drama Eternal Sunshine of the Spotless Mind (2004), followed by a lead role in Cameron Crowe's tragicomedy Elizabethtown (2005), and as the title character in Coppola's Marie Antoinette (2006). In 2010, Dunst portrayed Katherine Marks, the missing wife of accused murderer Robert Durst, in the biographical crime film All Good Things.

In 2011, Dunst starred in Lars von Trier's science-fiction drama Melancholia portraying a depressed newlywed, which earned her numerous accolades, including the Cannes Film Festival Award for Best Actress. She then had a supporting role in On the Road (2012), an adaptation of the Jack Kerouac novel, which garnered mixed reviews. She also appeared in Upside Down (2012), and the thriller The Two Faces of January (2014). In 2015, Dunst was cast as Peggy Blumquist in the second season of the FX series Fargo, which was well-received and earned Dunst her second Golden Globe nomination for Best Actress in a Series. This was followed by a leading role in the thriller Midnight Special (2016), the historical drama Hidden Figures (2016), and she reunited with Coppola for The Beguiled (2017). Dunst returned to television in 2019 with a lead role in the black comedy series On Becoming a God in Central Florida.