Bone marrow-derived mesenchymal stem cells (MSCs) from systemic lupus erythematosus patients (SLE-BMSCs) exhibited abnormalities in cytokine production and immune modulation. Deregulation of Nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in SLE. Herein, we explored whether miRNAs are involved in the regulation of NLRP3 in SLE-BMSCs. ELISA assay was used to detect the levels of inflammatory cytokines. The expression levels of let-7f-5p and gene mRNAs were determined by qRT-PCR assay. The protein levels of NLRP3, Cleaved caspase-1 and ASC were measured by western blot. The interaction between let-7f-5p and NLRP3 was verified using dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. In vivo assay was performed to explore whether let-7f-5p upregulation could ameliorate inflammation in MRL/lpr mice. Our data indicated that SLE patients had significantly serum higher levels of IFN-γ, IL-6, IL-18, IL-12, IL-13 and IL-1β. We demonstrated that NLRP3 expression was upregulated in SLE-BMSCs. Let-7f-5p directly targeted NLRP3 and repressed NLRP3 expression. NLRP3 depletion or let-7f-5p upregulation repressed IL-1β production and the expression of NLRP3 inflammasome components. Moreover, upregulated let-7f-5p-mediated anti-inflammation effect was significantly abrogated by NLRP3 expression restoration. Besides, let-7f-5p upregulation ameliorated inflammation through modulating NLRP3 in vivo. In conclusion, our study suggested that high level of let-7f-5p alleviated inflammation in SLE-BMSCs at least partly through targeting NLRP3, highlighting let-7f-5p as a novel promising therapeutic strategy for SLE treatment.