The actress enjoyed a major career breakthrough when she made her feature debut in Emma-Kate Croghan's engaging romantic comedy, "Love and Other Catastrophes" (1996), playing Danni, "a sweet young thing" as Mitchell describes her role, who is dazzled by Mia, a university film student. The two break up, but are eventually reconciled amid the often farcical incidents befalling their close circle of friends and lovers. Although Mitchell's follow-up film and US debut, Lisa Cholodenko's "High Art" (1998), was in many ways a different, much more dramatic film, her role as Syd did have some connections with Danni. Mitchell's large, expressive eyes and blonde hair suggested the youth and inexperience of an aspiring magazine editor dazzled by a gifted photographer (Ally Sheedy) on a career and personal downhill. At the same time, though, Mitchell was also called on to convey a mature and intense emotional attraction as well as a sometimes unattractive ambition, both of which she managed to critical acclaim. After a turn as a house guest who won't leave in the indie "Cleopatra's Second Husband" (also 1998).
Mitchell moved more into mainstream fare with the science-fiction horror of "Pitch Black" (2000), the thriller "Phone Booth" (2003) and as Dakota Fanning's mother in "Man on Fire" (2004), and she had her best role yet in "Finding Neverland" (2004) as the disconnected, alienated wife of "Peter Pan" creator J.M. Barrie (Johnny Depp). Meanwhile the actress wrote, directed and starred in her own labor of love, the indie "Four Reasons" (2002).
Mitchell took on her most complex and accomplished role when she starred as the title character(s) in writer-director Woody Allen's "Melinda and Melinda" (2005), which told of the romantic troubles of a young woman in two distinctly different parallel storylines, one tragic and one comedic. Mitchell effectively portrayed both Melindas, one as a wounded, self-destructive and possibly doomed figure, and the other as a more charming but neurotic woman blind to the available love that she could embrace. She next starred in “Silent Hill” (2006) as a desperate mother trying to find an answer for her daughter’s mysterious recurring dream that pulls her out of bed to sleepwalk. Instead of letting her child succumb to psychiatric care, she takes her to a fog-shrouded ghost town inhabited by a variety of strange beings—including demons—and overcome by a living darkness that transforms everything it touches. Despite negative reviews, “Silent Hill” opened number one at the box office with over $20 million in box office booty.