Abstract Background Afatoxin B (AFB) induces toxicological efects on the liver and immune organs. The whey proteins can modulate the immune response during afatoxicosis. Our work evaluates the novel polylactic acid-glycolic acid-chitosanencapsulated bovine and camel whey proteins against AFB-induced thymic and splenic atrophy in rats. Methods and results Seventy adult male Wister albino rats were divided into a control healthy group (G1) and six AFB1- intoxicated groups (G2–G7). One of the following supplements: distilled water, camel whey proteins (CWP), bovine whey proteins, poly (d, l-lactide-co-glycolide) (PLGA)- chitosan-loaded with camel whey protein microparticles (CMP), PLGAchitosan loaded with bovine whey protein microparticles (BMP), and PLGA-chitosan nanoparticles were administered as prophylactic supplements to AFB1-intoxicated groups. The AFB-treated group showed signifcantly higher hepatic levels of oxidative stress and lower levels of antioxidants. In the afatoxicated group, atrophy of the splenic lymphatic nodules and disfgurement in the organisation with an apparent decrease in the thickness of the cortex in the thymus were observed, as well as a decrease in splenic and thymic CD4+T and CD8+T lymphocytes. Moreover, CXCL12 levels were downregulated, whereas tumour necrosis factor-alpha, nuclear factor kappa B, and cleaved caspase-3 levels were upregulated. CWP, BMP, and CMP supplements markedly decreased oxidative stress, infammation, and apoptosis, as well as signifcantly raised CXCL12, CD4+T, and CD8+T cells. Conclusions The CWP, BMP, and CMP supplements rescue the liver and immune tissues from the toxic efects of AFB through their antioxidant, antiapoptotic, anti-infammatory, and chemotaxis-enhancing roles.