Pulmonary toxicity by anticancer drugs often leads to discontinuation of therapy or switching the therapy to alternative drugs. In the present study, serratiopeptidase (SPTD) and fisetin (FST) were evaluated as chemoprotectant to counteract the pulmonary toxicity induced by BLM and MTX. Single dose of MTX (20 mg/kg) by intraperitoneal and BLM (5 mg/kg) by intra-tracheal route was administered on 7th day of study. SPTD (20 mg/kg), FST (25 mg/kg), and NAC (250 mg/kg) and combinations of SPTD + NAC, SPTD + FST, and FST + NAC were administered through oral gavage for 14 days. SPTD and FST showed significant (p < 0.05) effect in MTX-induced lung toxicity by increasing reduced glutathione (GSH) and decreasing malondialdehyde (MDA), hydroxyproline (HXP), and collagen. SPTD and NAC showed significant (p < 0.05) effect in BLM-induced pulmonary toxicity by increasing GSH and decreasing MDA, HXP, and collagen whereas FST was not much effective. In combination study, SPTD + NAC combination showed significant (p < 0.05) effect in BLM- and MTX- induced lung injury whereas other combinations did not prove to be highly effective. SPTD can be recommended along with BLM and MTX in chemotherapy protocol alone and in combination with NAC.