Background: The pharmacologic and toxicological response to different drugs vary according to the type and breed of the animal. Objectives: This investigation was carried out to compare the toxic effects of azithromycin on chickens and quails. Methods: The animals of each kind were divided into 3 groups; the first group served as the control and received just distilled water; the second and third groups received different doses of azithromycin (5% and 10% of the median lethal dose) over 5 days. Results: Compared to quails, the LD50 in chicks was substantially higher. Both chicks and quails treated with high doses of azithromycin showed a substantial difference in neurobehavioral and motor measures. Total antioxidant capacity (TAC) and glutathione decrease in chicks receiving the high dose of azithromycin, whereas, in quail, the prior impact was present in both doses. With the cholinesterase activity in quails and chicks being inhibited, a high dose of azithromycin dramatically raised the level of caspase-3 in the quail. We observed severe diffuse vacuolar degeneration in hepatocytes with infiltration of inflammatory cells in quails and chicks in the high dose and less severe effects in quail and chicks in the lower dose. In quails’ livers, tumor necrosis factor-(TNF)-α was strongly expressed at high and weakly at low doses. Still, in chickens’ livers, TNF-α expression was moderate at high and low at low doses. Conclusion: At the same percentages and dose of the LD50 in both quails and chicks, azithromycin causes severe toxic effects in quails but less toxic effects in chickens.