Later that year, he was acquired by Italian club Juventus, where he remained for ten seasons, winning three Serie A titles and reaching the 2003 UEFA Champions League Final, although he was sent on several loan spells with Empoli, Spanish side Sevilla and Perugia during his time at the Turin club, due to heavy competition from other strikers in the team's line-up.

He moved to Juventus later that year, but although he was considered a promising young player at the time, he was not given much of a chance to prove himself due to heavy competition from several other prominent forwards at the club.

However, he scored a decisive goal on his Serie A debut on 14 March 1998, in a 2–2 home draw against Napoli; Juventus would finish the season as league champions.

At last, when it seemed Juve lacked forwards, he was brought back to Italy at the start of the 2001–02 season, but he was loaned out to Perugia in 2004 before returning to Juventus in the same year.

[12] Zalayeta represented Uruguay during his country's campaign to qualify for the 2006 FIFA World Cup, notably scoring a hat-trick in a 3–2 home win over Colombia on 4 September 2005.

Zalayeta's failure to convert culminated in Australia winning the play-off 4–2 on penalties, qualifying for the 2006 FIFA World Cup finals in Germany, and eliminating Uruguay in the process.

[1][12] A tall and physically strong forward, with a slender build, Zalayeta usually played as a centre-forward, and was primarily known for his technical skills and touch on the ball, as well as his eye for goal, heading, and ability in the air, which enabled him both to score and assist goals with his head; however, despite being a quick player in his youth, he was also known for his lack of pace as his career progressed.

[24] In December 1999, Zalayeta and compatriot Sevilla teammates Nicolás Olivera and Marcelo Otero were charged for assaulting a man.