Toxic heavy metal lead enters in the environment due to industrial and anthropogenic activity threatens ecosystems and public health. Natural garlic extract (GE) exhibits antioxidant properties and various applications against several ailments. Therefore, this study scrutinized the protective effects of tocopherol polyethylene glycol succinate-coated garlic selenium (TPGS-GSNP) against lead acetate (LA) toxicity in rabbits. Sixty-four mature male rabbits were involved and divided into 8 equal groups. They received distilled water (negative control; T1), 30 mg/kg bw of LA (positive control; T2), 800 mg/kg bw of GE (T3), GE + LA (T4), 1 mg/kg bw of TPGS-Selenium (T5), TPGS-S + LA (T6), 1 mg/kg bw of TPGS-GSNP (T7), and TPGS-GSNP + LA (T8). Consequently, treatments were administered three times a week for 12 weeks. Following the treatment period, serum oxidant-antioxidant, protein, and lipid profiles, liver and kidney function, histopathological findings of the adrenal, liver, and kidneys, femur bone marrow chromosomal aberrations, and mitotic activity were collected and analysed. LA exposure showed significant reductions in antioxidant levels, organ weights, and mitotic activity while increasing oxidative stress, corticosteroid levels, and chromosomal aberrations. Importantly, TPGS-GSNP administration significantly improved these markers compared to the LA group. In addition, histological analysis revealed structural improvements of the studied organs in the TPGS-GSNP group compared to the LA group, which displayed high cellular necrotic and degenerative changes. In conclusion, synthetic TPGS-GSNP demonstrated higher protective efficacy against LA-induced toxicity compared to natural GE or selenium alone. However, more future studies could be conducted to explore the potential of TPGS-GSNP as an anticancer or immunomodulatory agent.