Per- and Polyfluoroalkyl substances (PFAS) are widespread environmental contaminants linked to various adverse health conditions, including immune dysregulation and inflammation, though cellular mechanisms remain poorly understood. In this study, we investigated the direct in vitro impact of long-chain/legacy PFOA and PFOS, byproduct NBP2, PFO4DA, and PFMOAA, and next generation HFPO-DA/”GenX” on THP-1 human monocyte function at the cellular level. While all PFAS activated THP-1 cells and altered immune function, it is important to note that they did so in very different and often contrasting ways. PFOS suppressed inflammatory cytokine release, while NBP2 and PFO4DA activated uncoordinated and simultaneous inflammatory and anti-inflammatory immune responses. PFOA, HFPO-DA/”GenX”, and PFMOAA increased markers of suppressive phenotypes often associated with tumor-associated macrophages. Taken together, our findings demonstrate that PFAS, even at non-lethal concentrations, can directly interfere with functional immune responses in cellular models by altering cytokine profiles and immune activation states.