Introduction Although five-year survival rates for childhood cancer have surpassed 85%, childhood cancer survivors continue to suffer from long-term effects decades after treatment completion. The prevalence of pulmonary dysfunction is very common at 65.2% in adulthood. This study explores early changes in the trajectory of pulmonary function in pediatric cancer patients who received pulmonary toxic therapy. Methods In this single-center, retrospective cohort study, we included pediatric cancer patients diagnosed at <18 years old between January 1994 and December 2014. Patients were included if they received pulmonary toxic exposure: either chemotherapy (bleomycin, busulfan, lomustine carmustine or cyclophosphamide) or thoracic radiation. Outcomes included percent predicted values for spirometry, lung volumes, and diffusion capacity of the lungs post-treatment. Results Of 86 children who met inclusion criteria, 99% received pulmonary toxic chemotherapy, and 79% received thoracic radiotherapy. Patients showed an overall decrease in all three lung function parameters immediately post-treatment. Between one- and four-years post-treatment, there was a larger sustained decline in percent predicted lung function parameters for females (mean Forced Expiratory Volume in 1 Second, FEV1=81.0% ±15.7) than males (FEV1=93.2% ±10.2). Sensitivity analysis of 65 children who received radiation and bleomycin revealed pulmonary function trends similar to the overall population. Conclusions Our results reveal that male and female patients experience different lung function trajectories following pulmonary toxic cancer treatment, with females performing more poorly over time despite similar baseline function. Further research is needed to better understand the factors associated with poor lung function and impaired recovery post-treatment, particularly in females.