The Recife club, renowned for their fanatical fanbase, beat Betim 2-1 to win a playoff 3-1 on aggregate and secure a return to the second division for the first time since 2007.
Flavio Caca-Rato, whose surname translates as "Rat Catcher", scored the winning goal three minutes from time to guarantee Santa Cruz one of four promotion spots.
The Northeasterners will be joined in Serie B next year by their city rivals Nautico, who were relegated from the top flight after losing 5-0 to Atletico Mineiro on Saturday.
A crowd of less than 10,000 watched Cruzeiro beat Santos to extend their lead at the top of the league to 13 points with just six games remaining.
Goias beat Botafogo to move into fifth place just a point off a Copa Libertadores spot, while Corinthians' 1-1 draw at Vitoria was their 15th of the season and their fifth in their last seven games.