Lepidium meyenii (Lm), also known as maca, is an Andean crop used medicinally for multiple purposes. Studies have shown an immunomodulatory anti-inflammatory effect in murine macrophages, able to induce M1 macrophage polarization. We aimed to assess the effect of Lm on the inflammatory response of human macrophages to mycobacteria. Human monocytic THP-1 cells bearing two plasmid reporter systems for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and interferon regulatory factor (IRF) activation, were differentiated into macrophages with Phorbol 12-myristate 13-acetate (PMA), and then treated with Lm at concentrations of 1 ug/ml, 5 ug/ml and 10 ug/ml for 48 hours. Cells were then stimulated with Mycobacterium tuberculosis (Mtb), Mycobacterium smegmatis, and bacillus Calmette-Guérin (BCG) for 24 hours. Lm-pre-treated cells showed a reduction in the NF-kB activation upon inoculation with Mtb, M. smegmatis, and BCG, in a dose-dependent manner. No effect was observed in IRF activation. Lm decreased the amount of internalized Mtb, while increasing the number of BCG in human macrophages. Lm treatment at small doses lead to an M1 macrophage polarization. Our results indicate that Lm exerts an immunomodulatory effect on the NF-kB activation of human macrophages upon mycobacteria challenge. These findings could translate into a potential use of Lm in conditions of exacerbated inflammatory response such as cases of BCGitis or complications due to excessive inflammation during intravesical BCG therapy.