LaMarcus Aldridge had 22 points for Portland, which also snapped the Lakers' seven-game winning streak on the road.
Portland went up 96-90 early in the fourth, but Sasha Vujacic's 3-pointer tied it at 100 midway through the quarter. Vujacic nailed another 3-pointer to tie it at 107 with 3:05 left, but the Lakers could never grab the lead.
Roy hit a pair of free throws, and Travis Outlaw hit a jumper to make it 111-107 with 2:14 left. Aldridge added a pair of free throws to extend it.
Kobe Bryant missed a 3-pointer with less than a minute to go. Roy and Jarrett Jack hit four straight shots from the line to give Portland its biggest lead, 117-107, and seal the win.
Bryant had 33 points for the Lakers, who have lost five straight at the Rose Garden.
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Jarrett Jack had 21 points and 10 assists for the Blazers, who were coming off an 82-80 victory over the Los Angeles Clippers on Wednesday. A day earlier, Portland lost 96-83 at the Lakers at the Staples Center.
The Blazers also saw the return of 3-point specialist James Jones, who has been out since before the All-Star break with left knee soreness.
The Blazers are 23-12 when Jones plays and 8-14 when he doesn't. Jones finished with eight points.
The Lakers led by as many as 10 points early, but the Blazers closed to 32-27 at the end of the first quarter. Joel Przybilla's dunk pulled Portland to within 37-35, but after Przybilla fouled Bryant on the other end, the two exchanged words. Przybilla ended up with a technical.