Filmed in director Alexander Payne's hometown of Omaha, Nebraska, Klein was discovered when Payne visited his high school on a locations scout. After an audition, the young actor was cast as Paul Metzler, a sweet, naieve and popular sidelined athlete who is persuaded by his teacher (Matthew Broderick) to run against the overachieving Tracy Flick (Reese Witherspoon) for class president. Playing the least malevolent character in the film, Klein offered a portrayal that was likened by many critics to Keanu Reeves' charming early performances. Brown-haired, tall, and athletic in build, the actor again played a likable jock in that summer's surprisingly sensitive teen sex comedy "American Pie". This time he portrayed Oz, a lacrosse player who, in an attempt to impress girls, seeks to prove he is more than a mindless sports hero by joining a choir.

His rising status was further confirmed when he was signed to star opposite Leelee Sobieski in the romance "Here on Earth" (2000). Klein subsequently headlined the low-brow incest-themed comedy "Say It Isn't So" (2001, produced by the Farrelly brothers) and was tapped to star in the remake of the 1970s actioner "Rollerball" and appear in the ensemble of the Vietnam-era drama "We Were Soldiers" (both 2002), the true-to-life telling about the Air Calvary's landing in the Ia Drang Valley on November 14, 1965 the first major, and perhaps bloodiest, battle of the Vietnam War. In "The United States of Leland" (2003), Klein was the boyfriend of a girl (Michelle Williams) whose autistic brother is stabbed 20 times by an alienated teenager (Ryan Gosling). He then had a supporting role in "Just Friends" (2005), a mainstream comedy about a suave music executive (Ryan Reynolds) whose former life as a shy and overweight high school senior is resurrected when he runs into the best friend (Amy Smart) he had a crush on.