Repurposing of drugs already in clinical use is the fastest strategy to bring new therapy to the clinic. Our hypothesis is that treatment with repurposed drugs known to act on host cell mechanisms to block T. cruzi escape, combined with reduced doses of benznidazole, may show higher efficacy and less toxicity than high-dose benznidazole alone. We thus characterized the in vitro and in vivo response of the parasite to the repurposed drugs, selected because of their known blocking effects on important steps of the host cell invasion/replication by T. cruzi. Experiments measuring trypomastigote release to the supernatant of infected phagocytic and non-phagocytic mammalian cells indicated Chloroquine was as potent as BZN in suppressing T. cruzi parasitism, and that the combination of Chloroquine and Colchicine with BZN potentiated its effect several-fold. Syrian hamsters were infected intraperitoneally with Y strain of T. cruzi (3.5x10⁴). Treatment started 7 months post infection by gavage and lasted for 30 consecutive days; animals were sacrificed 12 months post infection. Animals were subject to echocardiography assessment at 11 months post infection, FS, LVEF, FAC, V(s), and MPI/FS in the infected group is significantly lower than 11-month non-infected control, indicating the progression of the disease. In addition, we tested the concentrations effective for inhibiting trypomastigote release from infected host cells, Colchicine and Chloroquine did not affect trypomastigotes growth; in addition, Chloroquine treatment of host cells prior to infection significantly reduced intracellular parasitism, suggesting the effect in intracellular infection was due to actions on the host cell, rather than the parasite. The infection index after 48h of infection was 562.5, while treatment with Chloroquine prior to or simultaneously with infection reduced the infection index more than 10-fold to 40.5 and 28.2 respectively.