In his first season, Colón did not quite live up to his expectations, going 4-7 with a 5.65 ERA. He would live up to those expectations soon after. In his real breakthrough 1999 season, one year after helping his Indians to the 1998 American League Championship Series, even in a lost cause against the Yankees, Colón finished 18-5, pitching over 200 innings with 161 strikeouts and a 3.95 ERA in innings pitched.

In 2000, Colón eclipsed his strikeouts number by 51, ending with 212, but at the same time he posted a career-high 98 walks. It was clear he was developing as a pitcher, but he had to learn to get his control back. 2002 was his best season to date, but it came in two cities: Cleveland and Montreal. Just prior to the 2002 trade deadline, Colón and Tim Drew were traded to the Montreal Expos in exchange for Lee Stevens, Brandon Phillips, and prospects Grady Sizemore and Cliff Lee. Colón finished 2002 with a combined 20-8 record and a 2.93 ERA, including only 76 earned runs with just 70 walks in 233 innings, three shutouts, and eight complete games. After that season, every team in the league wanted him, but only a few were willing to bid high enough to obtain him. Before the 2003 season, Colón was traded to the Chicago White Sox as part of a three team deal also including the New York Yankees. He finished 2003 with a 15-13 record. A free agent after the season, he signed with the Anaheim Angels. Colón won 18 games with Anaheim in 2004. In addition to being considered one of the best right-handed starters in the American League, his 2005 salary with the Angels was $11,000,000. During the 2005 season, he went 21-8 with a 3.48 ERA, and gained his first Cy Young Award.