The present work was designed to investigate the effect of aminoguanidine (AMG) on methotrexate (MTX)- induced lung toxicity in rats. Forty adult male rats weighing 200–220 gm divided into four groups, 10 each were used in the study. The control group received normal saline. AMG-treated group: rats received 50 mg/kg/day AMG. Whereas the MTX-treated group: rats received 0.5 mg/kg MTX twice weekly, and AMG+MTX-treated group: rats were co-administered AMG and MTX at the same doses as in the previous groups. All groups received their treatment via the IP route. Additionally, the experiment duration was 4 weeks.  MTX administration revealed a significant decrease in SOD, CAT, GSH, Nrf2, and Bcl-2 accompanied by a significant increase in MDA, NO, IL-6, IL-1β, NF-κB, caspase-3, and Bax compared to the control group. Moreover, there were histological abnormalities in the lung tissue. However, the AMG+MTX-treated group produced a significant increase in SOD, CAT, GSH, Nrf2, and Bcl-2, and a significant decrease in MDA, NO, IL-6, IL-1β, NF-κB, caspase-3, and Bax compared to the MTX-treated group. Besides, the histological results strongly supported our biochemical findings. The present study demonstrated the protective effect of AMG against MTX- induced lung toxicity in rats through its antioxidant, anti-inflammatory, and anti-apoptotic actions.