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As part of a drug discovery program aimed at the identification of anti-Trypanosoma cruzimetabolites from Brazilian flora, four acetogenins (1–4) were isolated from the seeds of Porcelia macrocarpaand were identified by NMR spectroscopy and HRESIMS. The new compounds 1and 2displayed activity against the trypomastigote (IC50= 0.4 and 3.6 μM) and amastigote (IC50= 23.0 and 27.7 μM) forms. The structurally related known compound 3showed less potency to the amastigotes, with an IC50value of 58 μM, while the known compound 4was inactive. To evaluate the potential mechanisms for parasite death, parameters were evaluated by fluorometric assays: (i) plasma membrane permeability, (ii) plasma membrane electric potential (ΔΨp), (iii) reactive oxygen species production, and (iv) mitochondrial membrane potential (ΔΨm). The results obtained indicated that compounds 1and 2depolarize plasma membranes, affecting ΔΨpand ΔΨmand contributing to the observed cellular damage and disturbing the bioenergetic system. In silico studies of pharmacokinetics and toxicity (ADMET) properties predicted that all compounds were nonmutagenic, noncarcinogenic, nongenotoxic, and weak hERG blockers. Additionally, none of the isolated acetogenins 1–4were predicted as pan-assay interference compounds.