The objective of this systematic review and meta-analysis was to examine the association between maternal chronic medical conditions (CMCs) and peripartum mental illness. MEDLINE, Embase, CINAHL, and PsycINFO were searched to September 2017. Data were extracted and quality was assessed using standardized instruments. We generated unadjusted and adjusted pooled odds ratios and 95% confidence intervals using DerSimonian and Laird random effects models. The review included 16 papers representing 12 studies and 1,626,260 women. CMCs overall were associated with peripartum mental illness overall (adjusted pooled odds ratios (aPOR) = 1.43, 95% confidence interval (CI): 1.25, 1.63). CMCs overall were associated with antepartum (aPOR = 1.41, 95% CI: 1.10, 1.81) and postpartum mental illness separately (aPOR = 1.44, 95% CI: 1.13, 1.85) and with peripartum depression (aPOR = 1.45, 95% CI: 1.25, 1.67) and anxiety separately (aPOR = 1.63, 95% CI: 1.35, 1.95). No studies examined bipolar or psychotic disorders. Diabetes (aPOR = 1.34, 95% CI: 1.07, 1.69), hypertension/heart disease (aPOR = 1.60, 95% CI: 1.05, 2.45), migraine (aPOR = 1.75, 95% CI: 1.20, 2.54), and other neurological disorders (aPOR = 1.45, 95% CI: 1.19, 1.77), but not asthma, were each associated with peripartum mental illness. Findings suggest that mental health resources should be integrated in medical settings where pregnant and postpartum women with CMCs are treated.