Cruzeiro immediately promoted Emerson Avila, coach of Brazil's under-17 team, as his successor, while former Jamaica World Cup coach Rene Simoes was sacked by Bahia who are one point above the relegation zone.
Atletico Paranaense completed another change with 70-year-old Antonio Lopes starting his fifth spell in place of former Brazil striker Renato Portaluppi, who quit after 14 matches leaving the team one from bottom.
Cruzeiro, who started the season as favourites for the South American Copa Libertadores and Brazilian championship but have disappointed in both, sacked Santana after 15 matches - eight wins and seven defeats. They are 11th in the standings with 27 points from 20 games.
"I was shocked... I'm really surprised by the decision taken. Brazilian football still has this kind of situation. My feeling is one of not having been able to complete a cycle I'd like to complete," the 62-year-old Santana told reporters.
Avila, 44, was already on Cruzeiro's coaching staff when he took charge of Brazil's under-17 team last year. He steered them to the semi-finals of the under-17 world championship in Mexico this year.
Paranaense have the hottest seat in the Brazilian first division with the appointment of Lopes, a former policeman and assistant to Luiz Felipe Scolari with Brazil's 2002 World Cup-winning team, their fifth of the year. He saved the club from relegation in 2009.
Only four of the 20 first-division teams have the same coach as they did at the beginning of the season.
