Lee hit a two-run shot off Milwaukee's Randy Wolf in the fifth inning. The ball hit the facade of the second deck in left field.
Lee becomes the seventh player to hit their 300th home run while playing for the Cubs, joining Ernie Banks, Billy Williams, Ron Santo, Ron Cey, Andre Dawson and Sammy Sosa.
The 34-year-old Lee may not wait long for someone to join him on the list. Alfonso Soriano has 299 career homers.
Lee has seven home runs this year and hit 46 during his career-best 2005 season.