We aimed to identify the prevalence of affective and anxiety disorders across different rare disease and identify correlates of psychopathology. We performed a systematic review and meta-analysis. We systematically searched Medline, PSYNDEX, PsycINFO for observational studies examining clinically diagnosed affective and/or anxiety disorders in adults with rare chronic diseases. Two researchers reviewed titles and abstracts independently and, for eligible studies, independently extracted data. The prevalence rates were pooled using a random intercept logistic regression model. We published a review protocol https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018106614CRD42018106614&ID=CRD42018106614CRD42018106614). We identified and screened 34 402 records for eligibility and considered 39 studies in the qualitative and 37 studies in the quantitative analysis, including N = 5951 patients with 24 different rare diseases. Heterogeneity between studies was large. Prevalence rates ranged widely between studies, with pooled prevalence estimates of 13.1% (95% CI 9.6–17.7%; I2 = 87%, p < 0.001) for current and 39.3% (95% CI 31.7–47.4%; I2 = 84%, p < 0.001) for lifetime major depressive disorder, 21.2% (95% CI 15.4–28.6%; I2 = 90%, p < 0.001) for current and 46.1% (95% CI 35.8–56.8%; I2 = 90%, p < 0.001) for lifetime affective disorders, and 39.6% (95% CI 25.5–55.6%; I2 = 96%, p < 0.001) for current and 44.2% (95% CI 27.0–62.9%; I2 = 94%, p < 0.001) for lifetime anxiety disorders. Sensitivity analyses excluding studies of low quality revealed nearly the same results. We conducted the first systematic review examining affective and anxiety disorders in adults with different rare diseases and found high prevalence rates. Supporting patients in disease adjustment can be crucial for their overall health and well-being.