Background: Obesity and asthma are highly associated, but the mechanisms underlying the association remain unknown. We examined five mediators linking obesity with childhood asthma: (1) pulmonary function impairment, (2) airway inflammation, (3) physical fitness, (4) sleep-disordered breathing (SDB), and (5) early puberty. Methods: A Mendelian randomization (MR) study with mediation analysis of data obtained from 5,965 children as part of the Taiwan Children Health Study. Cross-sectional regression analysis, MR two-stage least squares method, and MR sensitivity analysis were carried out to investigate each causal pathway. Prospective cohort analyses were used to confirm the findings. Results: The increased asthma risk associated with obesity was found to be mostly mediated through impaired pulmonary function, low physical fitness, early puberty. In the MR analysis, body mass index was negatively associated with FEV1/FVC and physical fitness index (β= −2.17 and −0.71; 95% CI, −3.92 to −0.42 and −1.30 to −0.13, respectively) and positively associated with early puberty (OR, 1.09; 95% CI, 1.02–1.17). High FEV1/FVC and physical fitness index reduced the risk of asthma (OR, 0.98 and 0.93; 95% CI, 0.97–0.99 and 0.88–0.98, respectively), whereas SDB and early puberty increased the risk of asthma (OR, 1.03 and 1.22; 95% CI, 1.01–1.05 and 1.05–1.42, respectively). The three main mediators were low physical fitness, impaired pulmonary function, and early puberty, with mediation proportions of 91.4%, 61.6%, and 28.3%, respectively. Temporal causality was further strengthened in prospective cohort analyses. Conclusions: Interventions promoting physical fitness and pulmonary function might effectively reduce obesity-induced asthma risk.