Giardia lamblia is a pathogenic protozoan presenting as the main characteristic, the trophozoite capacity to adhere in host intestinal epithelium, infecting mammals, including humans. The clinical treatment of this disease is based on metronidazole (Mz) that acts as an alternative electron acceptor, and its reduction promotes DNA impairment. In veterinary treatment, one of the best options is pyrantel pamoate (Pm), which the mode of action has not elucidated yet. Different strategies for Giardia treatment have been explored to avoid side effects to the host. In this context, the efficiency of treatment combining drugs raise as an interesting alternative for protozoan diseases. Here, we evaluated in vitro synergic effect of Mz and Pm on trophozoites and on its adherence to IEC-6 cells. The treatment with Mz or Pm was effective on trophozoites, with IC50/24 h values of 5.3± 0.9 μM and 13.8± 1.4 μM, respectively. The treatment of trophozoites with different combinations of Mz and Pm were also evaluated, as showed by fractional inhibitory concentration index (FICI) under 0.5 in all conditions tested, corresponding to the synergic effect. This synergic activity was also observed when the combinations of 5.3 μM Mz+ 0.4 μM Pm and 13.8 μM Pm+ 0.1 μM Mz induced a remarkable reduction in % adhesion (85–90% and 52–59%, respectively) and in number of adhered parasites per 100 cells. The low cytotoxicity to the host cells of the combinations, associated to the strong synergic potential of the combination, encourage us to further investigate its effect in in vivo models.