Pentadecafluorooctanoic acid (PFOA) is a highly persistent environmental contaminant known for its bioaccumulative nature and ability to cause adverse renal effects. Prolonged exposure to PFOA has been associated with oxidative stress, inflammation, and membrane dysfunction, which collectively contribute to renal impairment. This study investigates the nephroprotective effects of chrysin, a naturally occurring flavonoid with potent antioxidant and anti-inflammatory properties, against PFOA-induced kidney toxicity in male Wistar rats. Twenty-five rats were divided into five groups (n = 5 per group): (i) control (20% dimethyl sulfoxide), (ii) PFOA-only (5 mg/kg), (iii) 25 mg/kg chrysin + 5 mg/kg PFOA, (iv) 50 mg/kg chrysin + 5 mg/kg PFOA, and (v) 50 mg/kg chrysin-only. All treatments were administered orally for 14 consecutive days. Exposure to PFOA resulted in a significant (p < 0.05) elevation in serum creatinine, lactate dehydrogenase, and electrolyte imbalances, accompanied by reduced antioxidant enzyme activities, elevated oxidative stress markers, increased inflammatory cytokines, and disrupted ATPase activity. Chrysin pre-treatment at both 25 and 50 mg/kg markedly attenuated these toxic effects in a dose-dependent manner. It restored antioxidant defenses, normalized biochemical indices, improved electrolyte balance, and suppressed inflammation, thereby preserving renal function. These findings suggest that chrysin confers significant nephroprotective effects against PFOA-induced renal injury by mitigating oxidative stress, inflammation, and ion transport disruption, supporting its therapeutic potential as a promising nephroprotective agent for protecting against environmentally induced kidney injury.