<p>B cell malfunction is implicated in the pathogenesis of systemic lupus erythematosus (SLE) through the release of proinflammatory cytokines and the production of autoreactive antibodies. RNA <i>N</i>⁶-methyladenosine (m⁶A) is the predominant post-transcriptional RNA modification that has been reported to control various biological processes. Whether RNA m⁶A alteration and m⁶A reader protein YTHDF1 contribute to B cell activation and terminal B cell differentiation in SLE has not been fully demonstrated. Here we observed that SLE peripheral B cell subsets, activated B cells and differentiated plasma cells (PCs) had abnormally elevated levels of YTHDF1, the deficit of which attenuated PC differentiation both in vitro and in mouse models that have been immunized with keyhole limpet hemocyanin (KLH) or <i>N</i>-propionyl polysialic acid (NP–KLH). Utilizing RNA sequencing, RNA immunoprecipitation, m⁶A immunoprecipitation and other functional experiments, we have identified and described a PC-promoting role of YTHDF1. YTHDF1 binds to the m⁶A-marked 3′ untranslated region of transcription factor IRF4 messenger RNA to enhance its stability, thereby facilitating PC differentiation. Depletion of YTHDF1 hindered the differentiation of PCs, reduced the generation of autoantibodies and ameliorated the lupus-like phenotypes in an imiquimod-treated mouse model. Overall, this study highlights a distinct role of YTHDF1 in promoting PC differentiation through the direct regulation of IRF4 in an m⁶A-dependent manner and identifies YTHDF1 as a potential target for the treatment of SLE.</p>