Hyperuricemia is a metabolic disease attributed to a sustained dysregulation of purine metabolism, manifesting as consistently elevated blood uric acid levels. Hyperuricemic nephropathy (HN) is a renal complication of hyperuricemia. It is characterized by the deposition of urate crystals, inflammatory cell infiltration and tubulointerstitial injury. Ligusticum cycloprolactam (LIGc) is a novel monomeric derivative of the active ingredient ligustilide (LIG) from Angelica sinensis (Oliv.). LIG demonstrates anti-inflammatory and antioxidant properties. Nevertheless, the therapeutic potential of LIGc to ameliorate HN required further investigation. Our study revealed that LIGc effectively reduced serum uric acid and attenuated HN in mice induced by co-administering potassium oxonate and hypoxanthine. Our research demonstrated that LIGc treatment improved renal function in mice with HN by regulating the expression of uric acid transporters. Histopathological analysis showed that LIGc treatment reduced tubular damage, inflammatory infiltration and interstitial collagen deposition. Mechanistically, LIGc alleviated renal injury by inhibiting the TLR4/NF-κB signaling pathway both in vivo and in vitro. Our study revealed that LIGc effectively mitigated HN by attenuating the inflammatory response through the TLR4/NF-κB signaling pathway, providing new perspectives for the treatment of HN.