David DeJesus led off the first inning with a home run and Anthony Rizzo had two hits for the Cubs, who won back-to-back series for the first time this season.
Reid Brignac hit a pinch-hit homer for the Rockies, who finished a 2-4 road trip.
The Rockies have not won back-to-back games since a season-high eight-game winning streak April 12-20. They have not won a three-game series at Wrigley Field since Sept. 29 to Oct. 1, 2006.
Samardzija (2-5) allowed two runs and five hits. He struck out seven and walked two.
Colorado starter Jon Garland (3-4) allowed three runs and seven hits in five innings. He struck out four and walked one.
DeJesus snapped Garland's 18 1-3 scoreless inning streak against the Cubs with a leadoff home run into the left-field bleachers in the first inning. It was DeJesus' second leadoff homer of the season and 14th of his career.
Samardzija gave up the lead in the second inning on Josh Rutledge's RBI single. After a two-out double by Darwin Barney, Samardzija got the lead back on a two-run shot to left to make it 3-1. It was Samardzija's first of the season and second of his career.
Yorvit Torrealba grounded into a double play to end the second inning which set off a string of 10 consecutive batters retired by Samardzija.
In the sixth inning, Brignac led off with a pinch-hit home run to center. It was his first career pinch-hit homer and cut the Cubs lead to 3-2.
Samardzija got help from his defense in the seventh inning. With two outs, Rutledge lined a double off the wall in left field, Alfonso Soriano made a good relay throw to shortstop Starlin Castro, who was able to throw out Rutledge attempting a double.
The Cubs added to the lead in the seventh. Castro and Rizzo hit back-to-back RBI singles. Castro's hit came on a hit-and-run and Rizzo hit a hard grounder between the legs of Todd Helton at first base. Castro came around to score on Soriano's fielder's choice to make it 6-2.
In the ninth inning, Cubs closer Kevin Gregg gave up a two-out RBI single to Rutledge in a non-save situation. It was the first run he allowed in 11 appearances. He finished the game by getting Wilin Rosario to fly out to center with runners on first and third.
NOTES: Samardzija's other home run came on Sept. 23, 2009 at Milwaukee. ... RHP Jhoulys Chacin is Colorado's scheduled starter against San Francisco on Thursday. He is on a three-game losing streak against the Giants. ... The wave got going in the bottom of the seventh inning, an oddity at Wrigley Field. ... Rizzo has not struck out in his past 32 plate appearances, dating back to May 7th against the Cardinals.