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Natural products provide inspiration and have proven to be the most valuable source for drug discovery. Herein, we report a scaffold hybrid strategy of Tanshinone I for the discovery of NLRP3 inflammasome inhibitors. 36 compounds were designed and synthesized, and the cheminformatic analyses showed that these compounds occupy a unique chemical space. The biological evaluation identified compounds 5j, 12a, and 12d as NLRP3 inflammasome inhibitors with significant potency, selectivity, and drug-likeness. Mechanistic studies revealed that these Tanshinone I derivatives could inhibit the degradation of the protein NLRP3 and block the oligomerization of NLRP3-induced apoptosis-associated speck-like proteins, thus inhibiting NLRP3 inflammasome activation. In addition, the water solubility, in vitro metabolic stability, and oral bioavailability of these compounds were also greatly improved compared to Tanshinone I. Therefore, this protocol provides a new structural evolution of Tanshinone I and a new class of potent NLRP3 inflammasome inhibitors.