BACKGROUND: Research on tuberous sclerosis complex-associated neuropsychiatric disorders (TAND) in China remains limited. This study aimed to identify determinants of TAND severity to guide clinical management. METHODS: This multicenter registry-based study included 42 patients with genetically confirmed TSC recruited from nine tertiary hospitals in Henan Province between April 2021 and April 2024. TAND severity was estimated at follow-up using a domain-based scoring framework informed by the TAND checklist. Demographic, epilepsy-related, and genetic factors were analyzed using group comparisons, interaction analysis, univariable linear regression, and hierarchical regression. RESULTS: Among 42 patients with TSC, 25 carried TSC2 mutations and 23 had active epilepsy. Total TAND scores were significantly higher in patients with active epilepsy than in seizure-free patients (p < 0.001), and in patients with TSC2 mutations than in those with TSC1 mutations (p = 0.002). A significant interaction between genotype and seizure status was observed for total TAND score (p = 0.038). In hierarchical regression, genotype remained an independent correlate of TAND severity, while each additional year of education was associated with a 1.306-point reduction in total TAND score. CONCLUSION: TSC2 mutation, active epilepsy, and lower educational attainment were associated with greater TAND severity. TSC2 mutation remained independently associated with greater TAND severity after adjustment for epilepsy-related variables, whereas higher educational attainment showed a protective association. These findings support the need for early TAND screening and targeted follow-up in clinically vulnerable patients with TSC.