Argentinian forward Walter Montillo put the host side ahead in the fourth minute and Wallyson capitalised on a mistake by defender Wilmer Diaz to double its lead in the 31st minute.
Wallyson then turned provider for Roger to fire home a third goal on the counter-attack just after the hour.
Christian Marrugo reduced the deficit for Tolima seven minutes later, becoming the first player to score against Cruzeiro in the competition this year, but Roger soon restored the home team's three-goal cushion with a 71st-minute penalty.
Tolima defender Julian Hurtado was sent off in the closing minutes before Gilberto and Thiago Ribeiro sealed the rout.
The win moved Cruzeiro to 10 points at the top of Group Seven - four points ahead of Argentinian champion Estudiantes, who plays Paraguay's Guarani on Thursday.
Cruzeiro goalkeeper Fabio insisted his side had room for improvement despite its emphatic win.
"We left some empty spaces and it should not happen again," he said. "We played a great match and we are almost qualified to the next round."
Elsewhere, Libertadores champion Internacional of Brazil came back from a goal down to beat Wilstermann 4-1 in Bolivia.
Argentinian defender Ignacio Brown gave Wilstermann the lead in the seventh minute but then put through his own net eight minutes later to restore parity.
Leandro Damiao, Ze Roberto and Kleber then added further goals as unbeaten Inter claimed the sole lead in Group Six with 10 points.
Emelec of Ecuador remained three points behind the Porto Alegre side thanks to a 1-0 home win over Mexico's Jaguares, a 54th-minute penalty by Mario Quiroz proving decisive.
Finally, in Santiago, Chilean giant Colo Colo climbed to the top of Group Five courtesy of a 3-2 home win over Brazil's Santos.
Elano put the visitors ahead in the fourth minute but goals from Esteban Paredes, Ezequiel Miralles and Andres Scotti had Colo Colo 3-1 up at half-time.
Neymar gave Santos hope with his side's second goal four minutes into the second half but it could not find an equaliser as Colo Colo moved onto six points - one clear of Paraguay's Cerro Porteno.