Malathion is widely used organophosphorus insecticides available in various forms. However. it has sever side effect on the body's antioxidant systems. Hesperidin, a famous flavonoid, has a beneficial effect such as antioxidant, ant-inflammatory proprieties, which can inhibit the harmful effects. The aim of this work is to investigate the nephroprotective effect of hesperidin against malathion-induced nephrotoxicity. Four groups of rats, six per each: Control group (Group I), Hesperidin group (Group II), Malathion group (Group III), and Malathion+Hesperidin group (Group IV). Blood samples were taken to assess renal function by measuring serum level of creatinine and kidney injury molecule-1 (Kim-1). Renal homogenates were used to measure oxidative stress markers (malonaldehyde (MDA), superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH)), inflammatory markers, interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), apoptotic markers (caspase-2, B cell lymphoma-2 (Bcl-2), (Bcl-2) associated protein x Bax), and pyroptotic markers (NOD-like receptor protein 3 inflammasome (NLRP3), caspase-1). Renal tissues were fixed in formalin for histopathological examination. Hesperidin significantly decreased serum creatinine and Kim-1, restoring renal function affected by malathion administration. Also, hesperidin combats malathion-induced renal oxidative stress by reducing MDA, and increasing SOD, CAT, GSH levels. Hesperidin also, antagonizes malathion-induced renal inflammation by decreasing levels of TNF-α, IL-6, IL-1β. Moreover, it decreases malathion-induced apoptosis and pyroptosis by its reducing protein levels of caspase-3, Bax, NLRP3, caspase-1, while enhancing Bcl-2 levels. Hesperidin and malathion co-treatment improved the renal pathological alternation. Hesperidin offer a promising nephroprotective effect against malathion-induced nephrotoxicity through its antioxidant, anti-inflammatory, antiapoptotic and anti-pyroptotic capabilities.