Boca, losing finalists last year, were leading at half-time in Wednesday's Group One match after their goalkeeper Agustin Orion saved a penalty for the second match in succession.
But defensive errors allowed Toluca, who had lost three straight Mexican league games, to snatch a shock victory.
It was Boca coach and four times Libertadores Cup winner Carlos Bianchi's first game in charge in the competition for nearly a decade.
Uruguayan striker Santiago Silva put Boca ahead in the 22nd minute from the penalty spot after centre-back Matias Caruzzo, conceding a second spot-kick in five days, had brought down Toluca's Paraguayan forward Edgar Benitez.
The Mexican side missed the chance to equalise when Orion, who stopped a penalty in Boca's 3-2 home win over Quilmes in the Argentine championship on Saturday, saved defender Carlos Rodriguez's weak spot-kick in the 50th minute.
Undeterred, Toluca continued to dominate in the second half, tearing Bianchi's defence apart with veteran former Mexico midfielder Zinha pulling the strings.
Striker Carlos Esquivel levelled in the 57th minute and Benitez struck a fine winner in the 72nd.
"We've got problems managing matches and playing as we want to," Bianchi told reporters before fielding questions about the availability of watching playmaker Juan Ramon Riquelme who is not yet match fit.
"We all hope Roman can provide us with better ball control, vision, shooting, set pieces," said Bianchi, who shared in a string of titles with Riquelme in the pair's previous spells at Boca.
Substitute striker Lucas Viatri came close to salvaging a draw for Boca but his shot came back off the post.
Ronaldinho shone as Atletico Mineiro beat Sao Paulo 2-1 at home in an all-Brazilian Group Three match.
The Brazil forward hoodwinked the opposition defence at a throw-in by taking a drink of water and was unmarked to receive the ball and slip a brilliant pass through to striker Jo for the opening goal in the 13th minute.
Central defender Rever headed the second, also laid on by Ronaldinho, in the 72nd minute and substitute Aloisio pulled one back 10 minutes later.
Brazil striker Fred scored the only goal as Brazilian champions Fluminense won 1-0 away to Caracas FC of Venezuela in Group Eight.
Uruguayan five times trophy winners Penarol beat modest Chilean side Deportes Iquique 2-1 in northern Chile in Group Four.
