Background: The number of chronic diseases has been associated with changes in depressive symptoms over time among middle-aged and older adults. This study aimed to explore the association between the number of chronic diseases and trajectories of depressive symptoms and the role of age in this association. Methods: A total of 12,974 middle-aged and older Chinese adults (≥ 45 years) participated in the China Health and Retirement Longitudinal Study (CHARLS) in waves 2011, 2013, 2015, 2018, and 2020. The number of chronic diseases was determined by self-reported hospital diagnosis of hypertension, dyslipidemia, diabetes, cancer, chronic lung diseases, liver disease, heart diseases, stroke, kidney diseases, digestive diseases, emotional, nervous, or psychiatric problems, memory-related disease, arthritis or rheumatism, asthma, and then obtaining the total number of chronic diseases. Depressive symptoms were measured by the 10-item Center for Epidemiologic Studies Depression Scale (CESD-10). Group-based trajectory modeling (GBTM) was adopted to capture the trajectories of depressive symptoms over time. Multinomial logistic regressions were conducted to examine the association between the number of chronic diseases and trajectories of depressive symptoms and the role of age in this association. Results: Four distinct trajectories of depressive symptoms were observed in 34.68% individuals in mild, 40.76% in moderate, 19.41% in increasing, and 5.15% in severe group. Compared to participants without chronic diseases, those with one, two, three or more chronic diseases had a 1.81, 3, and 7.49-fold higher risk of developing severe depressive symptom trajectory, respectively. Moreover, the association between the number of chronic diseases and severe depressive symptoms trajectory differed by age (45–59 and ≥ 60 years) (P for interaction < 0.05). Conclusion: Participants with middle age may play a promoting role in the association between the number of chronic disease and severe depressive symptoms. The severe depressive symptoms intervention may be more beneficial for middle-aged adults.