Oligospermia (OA) represents a significant contributor to male infertility, with a pressing need for effective and low-side-effect therapeutic strategies. This study aims to investigate the ameliorative effects of mangiferin (MG) on OA and its underlying molecular mechanisms. To this end, an OA rat model was induced using busulfan (BU), wherein the effects of MG on sperm quality, testis histopathology, and serum hormone levels were assessed. Furthermore, an in vitro model of testicular Sertoli cells was prepared using benzimidazole (DRB) to evaluate the impact of MG on cell viability and apoptosis. Integrative bioinformatics approaches predicted targets and pathways associated with MG, supplemented by molecular docking and validation experiments employing Western blot and RT-qPCR techniques to elucidate the regulation of the NLRP3-ASC-Caspase-1-GSDMD signaling pathway. Results demonstrated that MG significantly enhanced sperm quality and rescued testicular tissue damage in OA rats while restoring hormonal balance. In vitro experiments corroborated these findings by showing increased Sertoli cell viability and reduced apoptosis. Network pharmacology and enrichment analysis indicated that MG exerts its effects primarily by inhibiting NLRP3 inflammasome activation. Mechanistic investigations revealed that MG downregulated the expression of NLRP3, ASC, Caspase-1, and GSDMD, thereby suppressing pyroptosis while mitigating oxidative stress (lowering MDA and enhancing SOD) and inflammatory responses (reducing TNF-α and IL-1β). In conclusion, MG regulates cell pyroptosis via the NLRP3-ASC-Caspase-1-GSDMD axis, thereby mitigating oxidative stress and modulating the inflammatory microenvironment in OA, suggesting its potential as a promising therapeutic agent for male infertility.