Hyperlipidemia represents a major risk factor for cardiovascular and renal diseases. This study aimed to demonstrate the possible ameliorating effects of policosanol (PC) on renal inflammation and pyroptosis. Eighteen male New Zealand rabbits were randomly divided into 3 groups (n = 6/group), one received normal chow diet for 12 weeks while the others received either 0.5 % w/w high cholesterol diet (HCD) or HCD and concurrently treated with PC (5 mg/kg body weight/day) for 12 weeks. Rabbits fed with HCD showed significant increases in body and kidney weights; renal dysfunction, dyslipidemia, oxidative stress status, elevated levels of oxidized low density lipoprotein (Ox-LDL) and renal High-mobility group box 1 (HMGB1). These increases were accompanied with up-regulation of phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling in renal tissue and activation of NOD-like receptor, pyrin domain-containing-3 (NLRP3) inflammasome. Administration of PC concurrently with HCD significantly modulated the HCD-induced activation of Ox-LDL/HMGB1/PI3K/mTOR/NLRP3/Caspase-1 signaling pathway and subsequently attenuated the resulted renal injury.