Aberrant activation of the NLRP3 inflammasome contributes to the evolution of diverse inflammatory diseases. Inhibition of the NLRP3 inflammasome has been proven to be an effective treatment strategy for NLRP3-driven diseases. This study revealed that multiple natural diterpenes from Isodon plants can inhibit the NLRP3 inflammasome, among which Rosthornin B (Ros B) exhibited the best inhibitory effect, with an IC of 0.39 μM. Further study revealed that Ros B directly interacts with NLRP3, thereby restraining NEK7-NLRP3 interaction and inhibiting NLRP3 inflammasome assembly and activation. Remarkably, Ros B had a significant therapeutic benefit in mouse models of NLRP3-driven septic shock, peritonitis, and colitis. Our study has identified a series of natural diterpenes that target the NLRP3 inflammasome. These natural diterpenes, especially those with low IC values, may lead to the development of new drugs and potential clinical therapies for diseases driven by NLRP3 inflammasome activation.