OBJECTIVE Although medical advances have allowed most patients with spina bifida (SB) to survive into adulthood, these patients may have physical impairments, urological complications, infections, and neurocognitive deficits. These factors can cause psychological distress and impact the transition from pediatric to adult care. There remains limited research on mental health disorders (MHDs) and substance use disorders (SUDs) in SB patients during this vulnerable transition period. This study aimed to investigate the 10-year incidence of MHDs and SUDs in 18- to 25-year-old patients with SB. METHODS TriNetX, a federated de-identified database, was retrospectively queried to identify 18- to 25-year-old patients with SB. The presence of MHDs and SUDs based on ICD-10 codes in SB patients (cohort 1) was analyzed and compared with those of patients without SB (cohort 2). Subgroup analysis was performed on SB patients with hydrocephalus and neurogenic bladder (NB). SB patients were further compared to patients with a spinal cord injury (SCI). RESULTS After propensity score matching, the authors identified 1494 patients in each cohort. SB patients were more likely to have depression (OR 1.949, 95% CI 1.64-2.317), anxiety (OR 1.603, 95% CI 1.359-1.891), somatoform disorders (OR 2.102, 95% CI 1.052-4.199), and suicidal ideations or attempts and self-harm (OR 1.424, 95% CI 1.014-1.999). The prevalence of attention-deficit/hyperactivity disorder (ADHD) and eating disorders were comparable between cohorts. SB patients also had increased rates of nicotine dependence (OR 1.546, 95% CI 1.22-1.959) but not of alcohol or opioid disorders. In SB patients, the presence of hydrocephalus and NB was not associated with significantly increased rates of any measured MHDs or SUDs. When compared with SCI patients, SB patients were more likely to have anxiety (OR 1.377, 95% CI 1.028-1.845) and ADHD (OR 1.875, 95% CI 1.084-3.242). However, SB patients had lower rates of nicotine dependence (OR 0.682, 95% CI 0.482-0.963) and opioid-related disorders (OR 0.434, 95% CI 0.223-0.845). SB and SCI patients shared similar rates of depression, suicidal ideations or attempts and self-harm, and alcohol-related disorders. CONCLUSIONS Young adults with SB have higher prevalence rates of MHDs and SUDs compared with the general population. Therefore, incorporation of mental health and substance use management is critical to facilitate transition to adulthood.