Background: Lenvatinib is a multitarget tyrosine kinase inhibitor (TKI) approved for the treatment of metastatic differentiated thyroid cancer (TC). The intended targets include VEGFR 1-3, FGFR 1-4, PDGFR α, RET, and KIT signaling pathways, but drug resistance inevitably develops and a complete cure is very rare. Recent data revealed that most of the TKIs have additional immunological off target effects, which might contribute to a protective antitumor immune response. However, the Lenvatinib-mediated immunomodulation remain poorly described. Aim: To investigate the impact of the in vitro Lenvatinib treatment on the functional status of circulating immune cells in healthy volunteers. Methods: Peripheral mononuclear cells and monocytes collected from healthy volunteers were exposed to Lenvatinib. Their functional phenotype was examined by stimulation assays, and by monocyte-TC cells co-culture experiments using well characterized cell lines (BCPAP, FTC 133 and TPC-1). Results: We found that monocytes were particularly susceptible to Lenvatinib treatment, while neutrophils and lymphocytes were less affected. In co-culture experiments, Lenvatinib exerted a broad inhibitory effect on the pro-inflammatory response in TC-induced macrophages. Interestingly, Lenvatinib-treated cells bear less characteristics of typical M2 phenotype, whereas they secreted significantly higher level of the anti-inflammatory cytokine IL-10 upon LPS stimulation. Prolonged exposure to Lenvatinib impairs macrophages survival and phenotypical differentiation, which was accompanied by remarkable morphological changes and suppressed cellular metabolic activity. These effects were mediated by monocyte-intrinsic mechanisms which are independent of Lenvatinib’s on-target activity. Finally, dual inhibition of p38 MAPK and Syk pathways is likely the underlying mechanism of the off-target effects we observed in this study. Conclusions: Our data show the immunomodulatory properties of Lenvatinib on human monocytes, which can be harnessed for future combination with immunotherapies.