LaMarcus Aldridge scored 14 points to help the Trail Blazers win in their home preseason debut. Matthews and Aldridge each hit 7 of 12 shots from the floor.
The Nuggets struggled from 3-point range, hitting 2 of 20 shots from behind the arc.
Portland started sluggishly, and Faried scored eight points early in the first quarter to give Denver a 19-14 lead. Sparked by Karl's four-point play, the Blazers finished the opening quarter with a 10-0 run to take a 26-23 lead.
Matthews fueled Portland's second-quarter surge, as he hit 5 of 7 shots, and two 3-pointers, that staked the Blazers to a 54-39 halftime lead.
Aldridge and Matthews combined to score nine of Portland's first 11 points of the third quarter as the Blazers built their lead to 20 points. Denver was unable to get closer than nine points the rest of the game.
Portland rookie point guard Damian Lillard, the No. 6 pick in the draft, sat out Wednesday's game with a foot injury. Nolan Smith, starting in Lillard's absence, had eight assists to lead all players.
Also sidelined for the Blazers was reserve point guard Ronnie Price, who has missed two games with an ankle injury. ... For Denver, Miller and forward Wilson Chandler made their first preseason appearances. Miller started at point guard in place of Ty Lawson, who sat out due to elbow pain. ... Portland and Denver each have three preseason games remaining before opening the NBA regular season Oct. 31.