The Timberwolves exploded for 47 points in the first quarter and the Lakers were playing from behind all night, eventually falling, 113-90.
Minnesota's Kevin Martin led all scorers with 27 points. Kevin Love had 25 points and 13 rebounds as the Timberwolves shot 48.9% from the field and 50% from three-point range.
Ricky Rubio notched a triple-double with 12 points, 14 assists and 10 rebounds. He also collected five steals in 38 minutes.
The Lakers managed to climb within 14 points by the end of three periods, but never threatened in the fourth.
Steve Blake scored 19 on 7-of-11 shooting. Jodie Meeks scored 16 off the bench, although he was called upon to start the second half when Steve Nash could not return because of back pain.
The Lakers shot just 38% from the field and 38.5% from three-point range. Pau Gasol contributed a double-double with 11 points and 11 boards.
The Lakers fall to 3-5 on the season while the Minnesota climbs to 5-2. The Lakers host the New Orleans Pelicans on Tuesday.
Minnesota will stay in Los Angeles, playing the Clippers on Monday.
The Lakers fell back behind by 29 before closing the gap to 14 by the end of the third.
Steve Blake helped carry the Lakers back, scoring 19 points on 7-of-11 shooting. Jodie Meeks contributed 14 points on 5-of-7 shooting.
Through three quarters, the Lakers shot 42.6% from the field and 47.4% from three-point range.
Steve Nash did not play in the third, staying in the locker room with back pain. Meeks started in his place.
The Lakers managed to whittle down some of the Timberwolves' massive lead, closing to within 19 at the half.
Minnesota's shooting dipped down to 53.2% from the field while the Lakers still struggled at 39.6%. In a game where offense (and defense) was a challenge, the Lakers turned the ball over 10 times and left seven points at the free throw line -- shooting 7 for 14.
Love hit five of six shots (4-5 from behind the arc) for 18 points along with eight rebounds. Martin shot 7 for 8 from the field for 16.
Meanwhile, the Lakers hit just 36.4% from the field, falling behind by as many as 28 points. The Wolves hit a blistering 76.2%, outscoring the Lakers, 27-2, over a five-minute stretch.
The Lakers (3-4) host the Minnesota Timberwolves (4-2) on Sunday night at Staples Center.
After a 1-2 road trip, the Lakers have a chance to finish the first two weeks of the season at an even .500 despite playing without Kobe Bryant.
To do so, they'll need to get past Kevin Love, Ricky Rubio and the Timberwolves. Minnesota might not be the deepest team in the league, but their starting five is very strong.
For a more in-depth breakdown, check out Preview: Lakers vs. Timberwolves.