Lead (Pb2+) toxicity is the most common form of heavy metal intoxication in humans and animals. Therefore, the current study was conducted to evaluate the potential ameliorative effects of curcumin on lead acetate (LA)-induced deleterious effects in the liver and kidney. Forty male Wistar rats were divided into four equal groups; first group was used as a control and given both corn oil orally and vehicle of lead acetate intraperitoneally (i.p). Groups from 2–4 were treated with lead acetate (LA; 50 mg/kg BW i.p), curcumin (200 mg/kg BW orally), and curcumin plus lead acetate, respectively. Curcumin was administered 3 weeks before LA injection for 7 days. Pb2+-intoxicated rats have higher Pb2+ levels compared to other treated groups. Results revealed that lead acetate significantly increased the serum levels of hepatic transaminases (GPT and GOT), urea and creatinine, while albumin was significantly decreased. In parallel, serum IgG, IgM, and IgA were significantly decreased in LA-injected rats. LA groups showed decrease in messenger RNA (mRNA) expression of catalase, SOD, GST, GPx, and alpha-1 acid glycoprotein (AGP), while the gene expression of desmin, vimentin, transforming growth factor-β1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1), and alpha-2 macroglobulin (α-2M) was increased. Prior and coadministration of curcumin with LA for 7 days significantly improved the ameliorated changes in liver and kidney, immunoglobulins, and mRNA expression. Moreover, curcumin ameliorated LA-induced congestion of hepatic and renal blood vessels and decreased fibrous tissue proliferation and necrosis of hepatocytes. In the kidney, LAinduced degeneration in tubular epithelium and intraluminal hyaline casts and prior curcumin administration restored normal renal structure with mild congestion of renal blood vessels. The results clarify the potential of curcumin to counteract the immunosuppressive alteration in gene expression as well as hepatic and renal damage occurred after Pb2+ intoxication.