Eastern Conference-leading Columbus is unbeaten in five matches.
Nashville snapped a four-match undefeated streak.
Gyasi Zardes scored on a back-heel flick from close range in the third minute of second-half stoppage time.
Zardes nearly scored in the 23rd minute but he sailed his shot over the crossbar. Zardes has three goals in the last two matches.
Santos fired a left-footed shot from just inside the 18-yard box on a cross from Zardes that beat diving goalkeeper Joe Willis.
Santos scored 10 goals in the past 11 matches.
The Crew hosts Minnesota United FC Wednesday at Mapfre Stadium (7:30 p.m./FOX Sports Ohio).