Kojo Mensah added 14 points, Clark had 13 points and 10 rebounds, Kieron Achara added 12 points and Gary Tucker contributed 10 as Duquesne (9-3) won its third in a row and extended its best start in 28 years.
The Dukes' three losses have come in consecutive games against Drake, No. 6 Pittsburgh and No. 23 West Virginia, teams with a combined record of 31-4.
Duquesne held a 41-31 halftime lead after turning an eight-point deficit into a 16-point lead with 2:39 remaining in the first half. The Dukes opened the second half on a 6-0 run to go up 47-31.
South Carolina Upstate used an 8-0 run to cut the lead to 47-40 but could get no closer. Clark hit three 3-pointers over the final 11:30 and Duquesne maintained a double-digit lead after James' driving layup with 13:26 left gave the Dukes a 57-46 advantage.
James added nine rebounds and three blocks for Duquesne, which outrebounded South Carolina Upstate 40-35. James now has 54 blocks on the season.