Congenital Chagas disease (CCD) is caused when Trypanosoma cruzi crosses the placental barrier during pregnancy and reaches the fetus, which can lead to serious consequences in the developing fetus. Current treatment is carried out with nifurtimox or benznidazole, but their effectiveness is limited, and they cause side effects, requiring the search for new therapeutic strategies. In this sense, many studies have demonstrated the potential of different compounds of the Copaifera genus in the control of parasitic diseases. Here, we aimed to evaluate the effect of oleoresin (OR) and leaf hydroalcoholic extract (LHE) of Copaifera multijuga on Trypanosoma cruzi infection in human villous trophoblast cells (BeWo line) and human placenta explants. Treatment with both compounds reduced invasion, proliferation, and release of trypomastigotes. Furthermore, OR and LHE affected the trypomastigotes and amastigote morphology, compromising their ability to invade and proliferate in BeWo cells, respectively. Also, treatment with OR decreased ROS production in infected BeWo cells, while LHE induced an increase. In addition, both compounds induced pro-inflammatory and anti-inflammatory cytokine production. In human placental explants, both compounds also decreased T. cruzi infection, in addition to inducing the production of pro-inflammatory cytokines. Thus, both OR and LHE of C. multijuga control T. cruzi infection at the human maternal–fetal interface, highlighting the possible therapeutic potential of these compounds for the treatment of CCD.