Background: PTC (Papillary thyroid carcinoma) is a complex disease. We previously found that BBR (Berberine), an effective component of Chinese herbal medicine Coptis, has an inhibitory effect on PTC. The exact process is not understood, possibly linked to pyroptosis controlled by NLRP3 (Nod-like receptor protein 3). The purpose of our research was to investigate the effects of pyroptosis in BBR treatment of PTC. Methods: PTC cell lines with different genetic backgrounds, such as BRAF(V600E) mutant (K1, BCPAP) and wild-type (TPC-1) PTC cells, were utilized in in vitro experiments. Pyroptosis was determined using in situ staining with Hoechst 33342 and PI. Levels of protein and mRNA were determined using western blotting and qRT-PCR. The IL-1? (interleukin-1?) and IL-18 levels were determined using ELISA kits. In order to measure ATP and LDH release, corresponding kits were used. The effectiveness of PTC cells in proliferation was assessed using a colony formation assay. BALB/c nude mice were utilized to create PTC xenografts. Results: During in vitro experiments, BBR was found to suppress proliferation and promote pyroptosis in both BRAF(V600E) mutant and wild-type PTC cells. NLRP3, caspase-1, GSDMD (gasdermin D), L-1? and IL-18 were up-regulated by BBR. Moreover, NLRP3 activated caspase-1 to promote GSDMD expression. NLRP3 and GSDMD knockdown attenuated BBR mediated pyroptosis in PTC cells. Further, BBR activated the NLRP3/caspase-1/GSDMD pathway and induced pyroptosis. The formation of PTC transplantation tumor was significantly inhibited by BBR in vivo experiments. Conclusions: As a result of our findings, BBR inhibits tumourigenesis in PTC cells of different genetic backgrounds by inducing pyroptosis, suggesting a promising therapeutic approach for tumours.