Kristaps Porzingis returned from a one-game absence and scored 22 points to lead the Knicks, who lost their third consecutive game. Tim Hardaway Jr. added 18 points for New York but shot just 6 of 18 from the field.
New York (10-10) staged a furious rally in the fourth quarter, cutting Portland's lead from 26 at the start of the quarter to eight with under a minute left.
The Blazers (13-8) scored just six points in the first 10 minutes of the fourth quarter, but New York went just 9 of 23 from the field in the period and was unable to come any closer.
Lillard led a balanced offense early as the Trail Blazers built a 16-point halftime lead. All five Portland starters and three reserves had multiple first-half field goals as the Trail Blazers committed just four turnovers before halftime.
Portland went on to finish with five players in double figures and turned the ball over only nine times.
The Trail Blazers took control with a 7-0 run to break a 22-22 tie toward the end of the first quarter and kept up the momentum as CJ McCollum and Ed Davis combined for nine points in a 9-0 run to start the second.
The Blazers got even hotter after the half, going 12 of 19 from the field in the third quarter as they increased their lead to 26. Lillard had 17 points in a productive third quarter when he went 5 of 7 from the field and added 6 of 6 free throws.
New York was without the services of Enes Kanter, who missed his third straight game with back spasms. The Knicks fell to 0-3 this season without Kanter, who is averaging a double-double for the season.
NOTES: Knicks C Joakim Noah made his first appearance of the season. He scored two points in three minutes. ... Portland F Al-Farouq Aminu missed his 13th consecutive game with an ankle injury. ... New York stays at home for a Wednesday matchup with the Miami Heat. ... On Thursday, Portland returns home for the first time since Nov. 18 when it hosts the Milwaukee Bucks. The Trail Blazers went 4-1 on their five-game road trip.