The Marlins noticed Vargas's success in the minor leagues and, when faced with injuries to their own pitching staff, decided to make him the fourth Mudcats pitcher to play in the major leagues in 2005 (the others were Logan Kensing, Olsen, and Bazardo). He made his major-league debut on July 14, 2005, the same day on which the Marlins designated veteran starter Al Leiter for assignment. His first start in the majors would come on July 18 against the Arizona Diamondbacks. Unlike Kensing, Olsen, and Bazardo, Vargas enjoyed nearly immediate success upon his arrival in the major leagues, and after Ismael Valdéz returned from a leg injury, the Marlins moved Brian Moehler to the bullpen and left Vargas in their rotation. On August 21, Vargas started against the Dodgers and pitched his first complete game in the majors, giving up one run on six hits and striking out seven. He finished the 2005 season with a record of 5–5 and a 4.03 ERA in 17 games, 13 of which were starts. Vargas received one third-place vote from the Baseball Writers' Association of America in the 2005 MLB Rookie of the Year voting.