Tripartite motif protein (TRIM) 50 is a new member of the tripartite motif family, and its biological function and the molecular mechanism it is involved in remain largely unknown. The NOD-like receptor family protein (NLRP)3 inflammasome is actively involved in a wide array of biological processes while mechanisms of its regulation remain to be fully clarified. Here, we demonstrate the role of TRIM50 in NLRP3 inflammasome activation. In contrast to the conventional E3 ligase functions of TRIM proteins, TRIM50 mediates direct oligomerization of NLRP3, thereby suppressing its ubiquitination and promoting inflammasome activation. Mechanistically, TRIM50 directly interacts with NLRP3 through its RING domain and induces NLRP3 oligomerization via its coiled-coil domain. Finally, we show that TRIM50 promotes NLRP3 inflammasome-mediated diseases in mice. We thus reveal a novel regulatory mechanism of NLRP3 via TRIM50 and suggest that modulating TRIM50 might represent a therapeutic strategy for NLRP3-dependent pathologies.