He played in Major League Baseball (MLB) for the Milwaukee Brewers, Toronto Blue Jays, Chicago Cubs, St. Louis Cardinals and San Diego Padres.

[1] He and Glenn Woolard were traded to the Milwaukee Brewers on March 30, 2004, in exchange for pitchers Wayne Franklin and Leo Estrella.

[citation needed] After a successful 2006 campaign, Villanueva entered the 2007 spring training in competition for the Brewers fifth spot in the starting rotation.

Villanueva pitched well in his new role and was occasionally used as a long relief pitcher when Elmer Dessens was placed on the DL.

On August 20, after pitching 3 perfect innings against the Arizona Diamondbacks and picking up his first career save, he was optioned to the Triple-A Nashville Sounds to make two starts to "polish up" for a September call up when the rosters expand.

Villanueva spent a short part of the 2009 season as the closer while Trevor Hoffman recovered on the disabled list;[5] however, after poor performances, the role was given to Todd Coffey instead.

[8] Villanueva began the 2012 season as the long reliever in the Jays' bullpen, but was promoted to a starter after numerous injuries to the pitching staff.

On February 4, 2015, the St. Louis Cardinals signed Villanueva to a minor league contract that included an invitation to spring training.

Villanueva pitched solely out of the bullpen in 2015 and was credited with a 4–3 record with two saves, 55 strikeouts, and 50 hits and 21 walks allowed.