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.
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.
Timberwolves 90, Lakers 76 (end of third quarter)
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.
The Timberwolves shot 49.3% from the field and 47.1% from three-point range. Kevin Martin led Minnesota with 27 points while Kevin Love had 22.
Steve Nash did not play in the third, staying in the locker room with back pain. Meeks started in his place.
Timberwolves 67, Lakers 48 (halftime)
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.
Pau Gasol led the Lakers with eight points. Kevin Love had 20 points in 22 minutes.
Timberwolves 47, Lakers 23 (end of first quarter)
The Minnesota Timberwolves quickly extended a double-digit lead over the Lakers behind an impressive display of outside shooting from both Kevin Love and Kevin Martin.
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.
Nick Young and Pau Gasol led the Lakers with six points each.
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.