Nen is best known for his years with the San Francisco Giants (1998-2002). He also played with the Texas Rangers (1993) and Florida Marlins (1993-97); in 1997, he won a World Series championship with the Marlins. After the 2002 season, Nen injured his throwing arm and has not played since. His signature pitch, a slider, was nicknamed "The Terminator." It looked like a fastball until it broke straight down at the plate at a velocity of up to 92 mph.

Nen was known for an unusual delivery in which he tapped his toe on the ground before releasing the ball.

The only known pitchers currently participating in Major League Baseball that throw pitches resembling Nen's signature pitch are Randy Johnson and Brad Lidge. Nen also had a fastball that regularly reached 98 mph. These two pitches led him to be one of the greatest closers of his time. He is the son of former major league first baseman Dick Nen.

A three-time All-Star, Nen formally announced his retirement in 2005 due to injuries to his right shoulder that required three surgeries. The final game of Nen's career was Game 6 of the 2002 World Series against the Anaheim Angels, a game in which Giants lost a heartbreaker, 6-5.