Multiple studies have revealed the critical roles of epigenetic modifications in the development of diabetic nephropathy (DN). Methyltransferase-like 3 (METTL3)-mediated N(6)-methyladenosine (m6A) RNA modification in podocytes represents a new disease mechanism in DN. The tripartite motif-containing (TRIM) family member TRIM29 was reported to promote podocyte pyroptosis by activating the nuclear factor-κB/NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway. However, whether METTL3-mediated m6A modification of TRIM29 mRNA is involved in podocyte injury remain unknown. Here, we found that METTL3 upregulated the m6A content in mRNA from kidney tissues of mice with streptozotocin-induced DN and in hyperglycemia-induced MPC-5 murine podocytes. METTL3 expression in high glucose-treated MPC-5 cells resulted in elevated release of interleukin (IL)-1β, IL-18, and lactate dehydrogenase and upregulated expression of pyroptosis-associated molecules. Mechanistically, METTL3 was found to directly target TRIM29 for m6A modification and activate TRIM29 transcription. Moreover, the m6A reader YT521-B homology (YTH) domain family member YTHDF1 was recruited by METTL3 to maintain the stability of TRIM29 mRNA, which contributed significantly to increased podocyte pyroptosis. Furthermore, the potent METTL3-specific inhibitor STM2457 prominently alleviated podocyte injury through attenuating activation of the NLRP3 inflammasome/pyroptosis pathway in the DN mouse model. Our results suggest that METTL3 plays a critical role in hyperglycemia-induced podocyte injury through m6A modification of TRIM29 mRNA, which provides new insight for the development of METTL3- and pyroptosis-targeted strategies to treat DN and other diabetic kidney diseases.