After losing out on a small role in 1993's "Beethoven's 2nd" when it was determined that he and his brother Danny (a primary actor in the film) looked too much alike, Masterson returned to the big screen in 1995 with a featured role alongside Matthew Modine and Geena Davis in the failed swashbuckler "Cutthroat Island". Work in the little-seen independent road movie "Sunchaser" followed in 1996, along with more TV guest work and a starring role in the cancelled pilot "Youth in Revolt" (Fox). In 1997, he acted on the Los Angeles stage in Mark Taper Forum's production of "Arcadia", and had a supporting role as the best man in the hit comedy "My Best Friend's Wedding". Roles in the horror film "Campfire Tales" and the acclaimed drama "American History X" followed in 1998, the same year that he completed memorable guest turns on the thriller series "The Pretender" (NBC) and "Millennium" (Fox). He was additionally featured in the independent "Girl", a coming-of-age drama set in the Seattle underground rock scene in 1999.
2000 saw Masterson with a regular series role on Fox's comedy "Malcolm in the Middle". Following a nameless family that was deranged by sitcom standards and slightly left of center of the normal American household, "Malcolm in the Middle" was a critical and commercial hit for Fox and offered Masterson the chance to play a likable, off-centered character in a highly-rated series not unlike his elder brother's experience with the same network's "That 70s Show". Teaming up with previous TV mom Jane Kaczmarek (another veteran of the failed pilot "Youth in Revolt"), Masterson played Francis, her eldest son and greatest challenge. A smooth-talking troublemaker with a strangely charming remorselessness exiled to military school, Francis was a perfectly bizarre member of this family, and Masterson proved a talented member of the flawless ensemble, with precise comic timing.