Memphis took a 79-61 lead at the end of the third and extended it to as many as 26 as Koufos consistently got to the rim early in the fourth.
Both teams then sent in the reserves to finish it out.
"I thought (it) was a really good, professional win," Memphis coach Dave Joerger said. "I thought our guys were focused and ready to play.
"I thought we played pretty well in the first half, and even better in the second half."
Memphis carried a 52-44 lead into halftime behind 11 points from Conley and 10 from Randolph.
Memphis controlled Jefferson, who entered the game averaging 31-plus points in his last four games. He had eight points at the break on 3-of-9 shooting.
Gasol just kind of shook his head when asked about stopping Jefferson, who was 2 of 13 for only six points when Charlotte won the first meeting 92-89 on Feb. 22.
"He has so many weapons, it's not about what you can do," Gasol said. "You can make it tough on him a little bit.
"Al is probably the toughest guy (to guard) because he has so many counters and different things he can do. Plus they run about 68 plays a game for him."
NOTES: Memphis entered the game having a different leading scorer in the last seven games. The streak ended with Conley scoring 20. Earlier this season, the Grizzlies went eight straight with a different high scorer. ... Jefferson's 17 points ended his string of four straight games scoring at least 25. ... Charlotte had lost the last three games in Memphis by a combined 74 points. ... Memphis reserve G/F Mike Miller left the floor in the second quarter after twisting his ankle, but returned in the second half.