Mauricio Larriera's men trailed from the fourth minute when Giorgian De Arrascaeta put the visitors ahead in Montevideo.
Adrian Luna doubled Defensor's lead before Damian Malrechauffe pulled a goal back for Racing on the stroke of half-time.
But third-placed Defensor dominated the final half-hour as Ernesto Dudok's own goal and strikes from Ignacio Risso, Luna and De Arrascaeta sealed their win.
It marked De Arrascaeta's sixth league goal of the season.
Gaston Pereiro struck in the 84th minute at the Estadio Centenario before the league's top goalscorer Ivan Alonso netted from the penalty spot to lift Nacional two points clear at the top.
Federico Gallego's late winner saw Sud America edge Tacuarembo 2-1 and Wanderers ended their four-game losing streak with a 3-2 victory at home to Rentistas.
Juventud were too good for El Tanque Sisley in a 3-0 win and Atenas' dominant second half saw them past Fenix 3-0.
