Background Bisphenol A (BPA) is used as monomer in polycarbonate synthesis, and it acts as plasticizer in baby and water bottles and the production of epoxy resins which are used as inner coatings of many food and beverage cans. This study was carried out to evaluate the possible modulatory effect of dry orange peels powder (OPP) to attenuate the toxic effects of BPA on liver and spleen in rats. Method Sixty male Spargue–Dawley rats weighing 130 ± 10 g were randomly divided into six groups (n = 10 for each group). Group 1: negative control, fed on balanced diet and received corn oil. Group 2: positive control, fed on balanced diet, received BPA (350 mg/kg b.w. per orally; p.o twice weekly) suspended in corn oil. Groups from 3 to 6 fed on balanced diet supplemented with OPP in the tested doses of 12.5, 25, 50, and 100 g/Kg diet respectively, and received BPA (350 mg/kg b.w. twice weekly). Results There was a significant increase in liver sterol regulatory element-binding transcription factor 1 gene expression (SREBF1), serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, nitric oxide (NO), total cholesterol (TC), triacylglycerols (TAGs), low-density lipoprotein cholesterol (LDL-c), very low-density lipoprotein cholesterol (VLDL-c), interluken-4 (IL-4), immunoglobulin-E (IgE)levels, and total leukocytes count (TLC) in BPA group as compared to negative control group (P < 0.05).On the other hand, BPA caused a significant decrease in liver catalase activity, serum high-density lipoprotein cholesterol (HDL-c), serum immunoglobulin-M (IgM) levels, blood hemoglobin% (Hb), and red blood cell (RBCs) counts compared to the negative control group (P < 0.05). Also, the histopathological examination of liver and spleen sections supported biochemical parameters showed a significant destruction in the BPA group as compared to the negative control group. Conclusion It is observed that OPP dietary supplementation in the tested doses ameliorates deleterious effects induced by BPA. The improvement in these altered parameters in OPP supplemented groups was in a dose-dependent manner.