Abstract Natural plant parts such as seeds of Azadirachta indica (neem seeds) and peels of Citrus sinensis (sweet orange) have been used as house-hold remedies against various ailments and bio-pesticides for agricultural purpose due to their repellent, growth regulatory and anti-feedant properties against insects. Despite their beneficial role, these natural insecticides could also have toxic effects on some vital organs of human. Therefore, this study aimed to investigate the sub-acute toxicity of smoke of the Seeds of Azadirachta indica and Peels of Citrus sinensis on the liver, kidney, lungs and heart of swiss albino rats. In this study, three groups of white swiss albino rats were exposed to the smoke of A indica seeds, peels of C sinensis and their combination at different duration of one hour and two hours respectively. The Control group were not exposed to any of the natural insecticides and were fed normal diet and water. After four weeks of the treatment, the animals were all sacrificed and their liver, kidneys, lung and heart were evaluated using standard biochemical and histopathological techniques. The levels of serum biochemical indices for liver (aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), total bilirubin and protein), kidneys (urea, creatinine and electrolytes), and heart (creatine kinase and lactate dehydrogenase) were found to be significantly higher at (p<0.05) for all the groups treated with the two natural insecticides when compared to control group. Histopathological changes including fibrosis, hemorrhages, vascular congestion and necrosis were observed in the liver, kidneys and lungs tissues of the rats exposed to the smoke of the seeds of A indica. However, no histopathological changes were observed in all organs of rats exposed to the smoke of the peels of C sinensis compared to control group. Moreover, the severity of the effects of smoke of these natural insecticides on both biochemical and histopathological indices increases with increase in duration of exposure. The results of this study revealed that seeds of A indica have significant toxic effects on both the tissue and biochemical markers of all the major organs of the Swiss albino rats, while peels of C sinensis shows effect on only the biochemical indices at the specific duration of time studied.