Chronic lung disease is associated with tremendous social and economic burden worldwide. The aim of this study was to investigate the sex-specific risk factors for changes in lung function in a large longitudinal study. We included 9059 participants from the Taiwan Biobank. None of the participants had a history of smoking, asthma, emphysema or bronchitis. Lung function was assessed using spirometry measurements of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). Change in the FEV1/FVC (ΔFEV1/FVC) was calculated as a follow-up FEV1/FVC minus baseline FEV1/FVC. Linear regression analysis was used to identify associations between variables and ΔFEV1/FVC in the male and female participants. After multivariable adjustments, the male participants (vs. females; p = 0.021) were significantly associated with a low ΔFEV1/FVC. In addition, the male participants with low aspartate aminotransferase (AST) (p = 0.003), high alanine aminotransferase (ALT) (p = 0.006) and a low estimated glomerular filtration rate (eGFR) (p = 0.003) were significantly associated with a low ΔFEV1/FVC. For the female participants, low systolic blood pressure (p = 0.005), low diastolic blood pressure (p = 0.031), low AST (p < 0.001), high ALT (p < 0.001) and a low eGFR (p = 0.001) were significantly associated with a low ΔFEV1/FVC. In this large follow-up study, we found that the male participants had a faster decrease in the FEV1/FVC than the female participants. In addition, liver and renal functions were correlated with changes in lung function in both the male and female participants. Our findings provide useful information on sex-specific changes in lung function.