Both teams shot poorly in the first half, and the Cardinals (8-4) needed a 10-run in the second half to pull away. Of the 10 Cardinals who played in the first half, only Smith hit more than one field goal.
"Though we didn't look good at times, we had to rely on our defense," Pitino said.
The Huskies (3-8) led by as much as eight points in the first half and went into halftime leading 27-25.
Eugene Spates led the Huskies (3-8) with 13 points, all in the first half.
With the score tied 32-32 in the second half, the Cardinals took charge with a 10-0 run to go ahead 42-32 with 8:25 left.
"I thought the game really came down to some fatigue, their size and athleticism," Huskies coach Bill Coen said. Louisville outrebounded Northeastern 44-27 and the Huskies shot 28 percent in the second half.
"Some of those shots that were going down in the first half weren't going down in the second, when you get fatigued."
The Cardinals shot 29 percent in the first half, but improved to 44 percent in the second. Louisville struggled from the free throw line, hitting just 16-of-29 (55 percent).
"Coach told us coming in you really have to strap it down defensively and not let them get hot like the first half," Smith said. "That's what we did in the second half."
David Padgett scored 12 for the Cardinals and Juan Palacios led all rebounders with 10.