Objective To examine the developmental trajectories and causal relationships between social isolation and depression among middle-aged and elderly patients with chronic diseases, so as to provide a reference for developing intervention strategies. Methods Based on the longitudinal data from the China Health and Retirement Longitudinal Study (CHARLS) 2015 (T1), 2018 (T2), and 2020 (T3), totally 3,249 chronic disease patients aged ≥45 years were selected and their data were analyzed using a latent variable growth model and cross-lagged model. Results Both social isolation (S=0.048,P＜0.05) and depression levels (S=0.119,P＜0.05) showed increasing trends among the participants.Higher initial social isolation correlated with more severe depression (β=1.714,P＜0.05), and the rate of social isolation progression positively predicted the rate of depression progression (β= 0.743,P=0.05).The cross-lagged model revealed a bidirectional predictive relationship between social isolation and depression (T1 social isolation → T2 depression: β=0.291,P＜0.05; T2 social isolation → T3 depression: β=0.394,P＜0.05; T1 depression → T2 social isolation: β= 0.014,P＜0.05; T2 depression → T3 social isolation: β= 0.009,P＜0.05).Analysis of individual differences revealed that women and individuals with lower educational background exhibited higher baseline levels of social isolation and depression.Additionally, advancing age, impaired IADLs, and cognitive decline emerged as common risk factors for both conditions (all P＜0.05). Conclusion A bidirectional causal relationship exists between social isolation and depression among middle-aged and elderly patients with chronic disease.Early screening of high-risk population is recommended.Breaking the negative cycle of social isolation and depression through family support, community activities, and mental health services can improve patients′ psychological well-being.