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.
"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.
