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Abstract Background It is crucial to improve cancer patients' quality of life by developing medications that can treat cancer with minimum adverse effects. This study aimed to evaluate the therapeutic effect of chitosan nanoparticles (CNPs) and camel milk exosomes (CMEs) alone or in combination with Sorafenib (SOR) on Ehrlich ascites carcinoma (EAC)-bearing mice and to assess whether EAC-associated liver injury would be ameliorated due to this combination. Liver function and oxidant/antioxidant status were determined spectrophotometrically, while the levels of inflammatory cytokines were estimated by enzyme-linked immunosorbent assay. Gene expression was detected using real-time polymerase chain reaction. Results The tumor burden in EAC-bearing mice was reduced after treatment with CNPs ± CMEs ± SOR as indicated by (1) reduced ascetic fluid volume and tumor-cell viability; (2) induction of apoptosis [high p53, BCL2 associated X (Bax), caspase 3, low B-cell leukemia/lymphoma 2 protein (Bcl2)]; (3) increased intracellular reactive oxygen species; (4) decreased migration [high matrix metalloproteinase 9 (MMP9) and low TIMP metallopeptidase inhibitor 1 (TIMP1)]; (5) declined angiogenesis [low vascular endothelial growth factor (VEGF). These treatments also reduced liver injury induced by EAC as noticed by (1) restored liver function indices [alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and albumin]; (2) restored redox balance [low malondialdehyde (MDA) levels and high superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities]; (3) increased antioxidant gene expression [high nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1)]; (4) declined inflammation [low interleukin-1β (IL1β) and tumor necrosis factor alpha (TNFα) levels), and (5) enhanced structure of liver. SOR + CNPs-treated mice showed the most improvement, followed by SOR + CMEs-treated animals. Conclusions Based on these findings, we determined that CNPs and CMEs enhanced SOR's anticancer efficacy and had an ameliorative role against EAC-induced liver injuries. Graphic abstract