BACKGROUND: There is growing global concern about poor mental health among adolescents in sub-Saharan Africa. In particular, adolescent girls face multiple challenges in managing menstruation which can impact both their health and wellbeing. In this study we address an evidence gap on the association of a broad range of menstrual-related factors with mental health problems amongst secondary school female adolescents in Uganda. METHODS: We used baseline data from a cluster-randomised menstrual health intervention trial conducted in 60 secondary schools in two districts in Uganda. Baseline data were collected between March and July 2022, including socio-demographic characteristics, menstrual knowledge and attitudes, menstrual practices and self-efficacy, and mental health problems measured using the Strengths and Difficulties Questionnaire Total Difficulties score (SDQ-25). We used random-effects linear regression to estimate the adjusted mean difference (aMD) for the association between mental health problems (SDQ Total Difficulties Score) and menstrual-related factors, including the Menstrual Practice Needs Scale (MPNS) and the Self-Efficacy in Addressing Menstrual Needs scale (SAMNS)), accounting for school-level clustering and adjusting for prior confounders. RESULTS: Among the 3841 female participants, there was strong and consistent evidence of associations between mental health problems and menstrual-related factors. Mental health problems were associated with poor knowledge about menstruation (aMD = 1.17, 95%CI 0.50, 1.84 <0.001), using disposable and reusable menstrual products compared to using just disposable products (aMD = 1.42, 95%CI 0.92, 1.92, p <0.001), and experiencing menstrual pain even when using an effective management method at last menstrual period (LMP) compared to those experiencing no pain (aMD = 1.60, 95%CI 1.19, 2.01, p <0.001). Mental health problems were also associated with greater unmet menstrual needs according to the MPNS (aMD = 4.40 95%CI 3.96, 4.84, p <0.001), and with lower menstrual self-efficacy measured by the SAMNS (aMD = 0.94 95% CI 0.51, 1.37, p <0.001). CONCLUSION: This study shows strong evidence that mental health problems reported by adolescent girls in Uganda are associated with poor menstrual health. The association between menstrual health and mental health provides evidence as to why menstrual health should be a public health priority. TRIAL REGISTRATION: Trial registration: ISRCTN 45461276. Registered on 16 September 2021.