He managed the Houston Astros from 2010 to 2012, and served as a coach in MLB for the Expos, Philadelphia Phillies, Boston Red Sox, and Cleveland Indians.

He divided his time between Triple-A and the majors in each of those seasons, and sustained a right knee injury that ended his playing career at the age of 29.

From 2004 to 2009, Mills was teamed again with Francona when he served as the bench coach for the Boston Red Sox.

[3] The 2011 season was much less appealing for both Mills and the Astros, as they suffered the franchise's first ever 100-loss season, finishing with a dubious record of 56–106, as the team traded away more former All-Stars to slash payroll such as Hunter Pence and Michael Bourn, opening up opportunites for future All-Stars such as Jose Altuve and J.D.

[9] On July 11, 2017, Mills managed the American League All-Star team while Francona dealt with a health issue.

The Indians subsequently announced on October 30, 2020 that Mills will not return as bench coach for the 2021 season, but would remain with the club in an undetermined role.