Jakob Gollon added 20 points for the 14th-seeded Bears.
The senior-laden Bears were simply too much for a Duke team with stars Rodney Hood and freshman Jabari Parker.
Mercer scored 11 straight points during the late 20-5 run that clinched the biggest victory in school history. It's the second one-and-done in three years for the third-seeded Blue Devils.
Mercer won the Atlantic Sun conference championship. That's the same league that produced 2013 tournament darling Florida Gulf Coast.
Quinn Cook scored 23 points, Rasheed Sulaimon added 20 and those two guards combined for 12 of Duke's season-high-tying 15 3-pointers.
But the Blue Devils' defense - an uncharacteristic weakness all season - did them in again while all those Mercer seniors picked Duke apart down the stretch.
Duke went up 63-58 with 4:52 left after Parker converted a three-point play and Tyler Thornton hit three free throws.
Duke didn't score again until the final minute.
Coursey countered by rattling in a jumper in the lane, and after two empty possessions for Duke, some slick ball rotation by Mercer set up an open 3 from Anthony White Jr. that tied it at 63 with 2½ minutes left.
Hood picked up his fourth foul on the Bears' next possession and Gollon hit two free throws to put Mercer ahead for good.
By that point, Duke - in the midst of an untimely run of empty possessions - could do nothing right. Parker missed a 3-pointer in traffic before Hood was called for walking, leading White to give a fist-pump to the Mercer fans who stood all day.
(Copyright 2014 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.)