Background: We explored the association between several chronic diseases and depressive symptoms (DSs) at individual and couple levels.Methods: Data were derived from the 2018 China Health and Retirement Longitudinal Study, including 5365 middle-aged and elderly couples. DSs were measured using the 10-item Center for Epidemiological Studies Depression Scale, and chronic diseases were determined by self-report and doctor diagnosis. Multivariate logistic regression models were used to estimate the association between chronic diseases and DSs.Results: Couples’ unilaterality with different numbers of chronic diseases had increased 16%–289% risk on their own DSs and 24%–39% risk on spousal DSs. Couples with different numbers of chronic diseases increased their co-depression by 183%–834%, which was mainly increased in wives’ depressive symptoms (WDSs) by 51%–301%, more severe than husbands’ depressive symptoms (HDSs). WDSs and HDSs increased by 13%–111% in couples with unilateral respiratory disease, dyslipidaemia, digestive disease, arthritis, kidney disease, stroke, memory-related disease and by 24%–244% in couples’ co-morbidity of respiratory, metabolic, and digestive diseases, arthritis, heart problem, kidney disease, stroke. Further, co-depression increased by 34%–458% in couples with unilaterality/co-morbidity of these chronic diseases.Conclusions: Couples’ unilaterality/co-morbidity of most chronic diseases were associated with WDSs, HDSs, and co-depression. WDSs were more susceptible to chronic diseases than HDSs. Physical health of an individual could predict not only his/her own mental health but also his/her spouse’s mental health.