Purpose <p>Childhood-onset asthma is associated with an increased risk of severe mental illnesses later in life. However, the causal relationship between childhood-onset asthma and major mental disorders remains unclear.</p> Methods <p>A two-sample Mendelian randomization (MR) analysis was conducted to investigate the causal effects of childhood-onset asthma (<i>n</i> = 327,670) on six major mental illnesses, including major depressive disorder (<i>n</i> = 143,265), bipolar disorder (<i>n</i> = 353,899), schizophrenia (<i>n</i> = 130,644), anxiety (<i>n</i> = 10,240), autism (<i>n</i> = 46,350), and ADHD (<i>n</i> = 225,534), using summary statistics of genome-wide association studies (GWAS). The inverse variance weighted (IVW) method, along with the weighted median and the MR-Egger method, was employed to obtain causal estimates. Multiple sensitivity analyses were conducted to examine the robustness of the estimates. Additionally, the direct effects of childhood-onset asthma on mental disorders after accounting for the effects of adult-onset asthma were evaluated through the multivariable MR (MVMR) analysis. To eliminate potential reverse causality, a reverse MR analysis was conducted, treating mental disorders as the exposure and childhood-onset asthma as the outcome.</p> Results <p>Genetically determined, childhood-onset asthma was significantly associated with an increased risk of depression (IVW OR = 1.059, 95% CI: 1.025–1.095, <i>p</i> = 5.72e-04) and bipolar disorder (IVW OR = 1.065, 95% CI: 1.027- 0.105, <i>p</i> = 6.75e-04). However, it was not associated with other mental disorders. Further MVMR analysis indicated that the causal relationships remained significant after accounting for adult-onset asthma. Interestingly, childhood- and adult-onset asthma exerted distinct causal effects on depression and bipolar disorder. Reverse MR analysis revealed no causal relationships between the six assessed mental disorders and either childhood-onset asthma or the age of asthma onset.</p> Conclusions <p>The MR analysis revealed a significant causal relationship between genetically determined, childhood-onset asthma and an elevated risk of depression and bipolar disorder later in life. The causal effects of childhood-onset asthma were distinct from those of adult-onset asthma. Further studies are warranted to investigate the underlying mechanisms of these causal relationships.</p>