Colorado won two of three in the season-opening series, getting three home runs to dispose of the Brewers.
Wilin Rosario hit a two-run shot for the Rockies in the first inning, but Milwaukee came back to tie the score in the third.
Brignac then doubled home Jordan Pacheco to give the Rockies the lead again in the fifth and Brignac scored later in the inning on an infield single from Eric Young.
Juan Nicasio went six innings to get the win, allowing two runs on seven hits. The first four Colorado runs came off losing pitcher Wily Peralta, who lasted 5 1/3 innings.