<p>Tacrolimus (TAC), a calcineurin inhibitor commonly used as an immunosuppressant in organ transplantation, is often limited by its nephrotoxic effects. This study explored the protective potential of mangiferin (MF), a naturally occurring glucosylxanthone, against TAC-induced nephrotoxicity in rats. Thirty-six rats were allocated into six groups: control, TAC, MF₂₀, MF₄₀, TAC + MF₂₀, and TAC + MF₄₀. Renal injury was evaluated using biochemical markers (creatinine, blood urea nitrogen (BUN), proteinuria, and creatinine clearance) and histopathological assessment. MF treatment significantly improved TAC-induced renal dysfunction, preserved kidney structure, and mitigated oxidative stress by decreasing malondialdehyde (MDA), nitric oxide, and inducible nitric oxide synthase (iNOS) expression while enhancing antioxidant enzyme activity and total antioxidant capacity. Furthermore, MF attenuated inflammatory responses by reducing tumor necrosis factor α (TNF-α), interleukin (IL)-1β, and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome levels and suppressed vascular endothelial growth factor (VEGF)-mediated proangiogenic signaling. It also modulated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/phosphatase and tensin homolog (PTEN) signaling and downregulated autophagic (microtubule-associated protein 1 light chain 3, LC3) and apoptotic (caspase-1) markers. Furthermore, MF decreased renal levels of P62, IL-18, hypoxia-inducible factor 1-alpha (HIF-1α), and transforming growth factor-beta (TGF-β). These results indicate that MF confers nephroprotection against TAC-induced renal injury that is highly associated with the modulation of oxidative stress, NLRP3 inflammasome, VEGF signaling, and PI3K/AKT/PTEN-mediated autophagy and apoptosis.</p>