Background: Cisplatin (CDDP) is an effective chemotherapeutic agent whose gonadotoxicity can lead to premature ovarian insufficiency through oxidative stress, inflammation, and apoptosis. Sodium–glucose cotransporter-2 (SGLT2) inhibitors exhibit cytoprotective effects, but their ovarian effects during chemotherapy remain poorly defined. Methods: Twenty-four female Wistar rats were randomized (n = 6/group) to Control (vehicle), Cisplatin (7 mg/kg, i.p., day 14), Cisplatin + dapagliflozin (DAPA; 0.9 mg/kg/day, p.o., days 1–14), or Cisplatin + empagliflozin (EMPA; 10 mg/kg/day, p.o., days 1–14). At 24 h post-cisplatin, serum estradiol (E2), progesterone, follicle-stimulating hormone (FSH), and Anti-Müllerian Hormone (AMH) were measured (ELISA). Ovarian glutathione (GSH) and malondialdehyde (MDA) were assayed, TNF-α and IL-6 mRNA were quantified by qRT-PCR, caspase-3 protein by Western blot, and histopathology by H&E. Results: Cisplatin decreased GSH, E2, AMH and progesterone and increased MDA, FSH, TNF-α, IL-6, and caspase-3, with marked histological injury. Both SGLT2 inhibitors improved biochemical, molecular, hormonal, and histological indices versus Cisplatin. DAPA partially restored antioxidant status and reduced inflammatory/apoptotic markers. EMPA produced greater normalization: GSH and MDA approached control values; progesterone returned to control; FSH fell more than with DAPA; E2 and AMH increased versus Cisplatin but remained below Control in both treatment groups; TNF-α declined more with EMPA, whereas IL-6 reductions were comparable; caspase-3 decreased to near-control with EMPA and decreased but remained elevated with DAPA (p < 0.05 for stated comparisons; one-way ANOVA with Tukey). Conclusion: Prophylactic SGLT2 inhibition mitigates cisplatin-induced ovarian toxicity, with empagliflozin showing broader and deeper improvements than dapagliflozin. These findings support SGLT2 inhibitors as candidate adjuncts to preserve ovarian function during cisplatin therapy and justify studies of dose–response, timing, fertility outcomes, mechanistic pathways, and antitumor safety
