In college, Kevin Youkilis was a 2-time All-American in four seasons for the University of Cincinnati, where Sandy Koufax once also played baseball. He set Bearcats career records with 53 home runs, 206 walks, a .627 slugging percentage, and a .499 on base percentage.

The Red Sox drafted him in the 8th round in 2001.

He climbed through three levels of the organization in 2002, going from Augusta to Sarasota to Portland, where he hit .344 in 44 games. He was voted Boston Red Sox minor league player of the year.

In 2003, he tied Kevin Millar's minor-league record by reaching base in 71 consecutive games. He was voted onto the Eastern League all-star team.

In 2004, Youkilis was batting .258 with three home runs and a .347 on base percentage in 32 games with Triple-A Pawtucket when he got the call to the Red Sox.

Youkilis had a .441 career obp in the minor leagues. Along the way, Youkilis impressed by demonstrating a good knowledge of the strike zone. He collected 270 base on balls in his first 325 games, walking almost two times for every time he struck out.

After dipping in and out of the majors in 2004-05, due to an acquisition of Gold Glove third baseman Mike Lowell, the 2006 season saw Youkilis switch from his natural position at third base to be the starting first baseman for the Red Sox, replacing the departed Kevin Millar. Youkilis has also filled in at his natural position, third base, when necessary. Youkilis had no outfield experience but injuries forced him to left field for 18 games, where he did a fine job, playing error-less defense with 3 assists. Youkilis also demonstrated his versatility offensively by batting in every spot in the lineup except ninth. He was very valuable batting leadoff, due to his excellent ability to get on base.

In 2006 Youklis led the major leagues in both pitches per plate appearance (4.42) and sacrifice flies (11). He was 7th in the league in walks (91), 8th in doubles (42), and 10th in times on base (259). He also scored 100 runs.