The study aims at evaluating the protective effects of Ajwa dates extract against diclofenac sodium (DFS)-induced nephrotoxicity. A total of 30 male albino mice were divided into three groups. Group 1 received water per oral gavage for 14 days and saline per intra-peritoneal (IP) dose for the days 12–14. Group 2 received water like Group 1 and a daily IP dose of DFS for the days 12–14. Group 3 received 1 gm/kg Ajwa extract in water for 14 days and a daily IP dose for the days 12–14. Biochemical investigation revealed DFS-induced increase in serum urea and creatinine levels along with depleted antioxidant capacity, altered lipid profile, and hyperglycemia. Ajwa extract successfully protected against DFS-induced adverse effects, normalizing renal parameters biochemically and histologically, and prevented its hyperlipidemic and hyperglycemic effects. Ajwa protected against endogenous antioxidant capacity depletion in treated animals. Hydroalcoholic Ajwa extract is a promising candidate for protection against DFS-induced hyperlipidemia and nephrotoxicity.