Abamectin (ABM) is a widely utilized potent anthelmintic and insecticidal agent. In this study, we investigated the protective effects of caffeic acid phenethyl ester (CAPE) and betaine (BET) against ABM-induced hepatotoxicity and nephrotoxicity in rats. Forty rats were divided into five groups, receiving either oral saline solution (normal control), oral ABM at a dose of 2 mg/kg BW (1/5 LD50), CAPE (10 μmol/kg BW intraperitoneally) followed by ABM, or BET supplementation at a dose of 250 mg/kg BW followed by ABM administration, while group V rats received a combination of i.p. CAPE and oral BET in the same doses before receiving ABM. Biochemical analysis showed that ABM administration significantly (p < 0.05) increased serum levels of aminotransferases, alkaline phosphatase, lactate dehydrogenase, and cholesterol, as well as serum creatinine and urea. Compared to the control group, ABM-intoxicated rats had significantly (p < 0.05) higher tissue concentrations of nitric oxide and malondialdehyde, as well as lower tissue glutathione concentration, total antioxidant capacity, and antioxidant enzymatic activity (glutathione peroxidase, superoxide dismutase, and catalase). Histopathological examination of hepatic and renal tissues of ABM-intoxicated rats showed acute inflammatory and necrotic changes. Pretreatment with CAPE and/or BET reversed the biochemical and histopathological alterations of ABM on the liver and kidneys. Therefore, CAPE and BET (alone or in combination) could be promising protective agents against ABM-induced hepatotoxicity and nephrotoxicity. Future studies should confirm our findings and evaluate the other molecular effects are involved in the combination chemoprotection of CAPE and BET.