BACKGROUND: In the past decade, patient-accessible electronic health record (PAEHR) systems have emerged as an important tool for health management both at the hospital level and individual level. However, little is known about the effects of PAEHR portals on the survivorship of patients with chronic health conditions (eg, cancer). OBJECTIVE: This study aims to investigate the effects of the use of PAEHR portals on cancer survivors' health outcomes and to examine the mediation pathways through patient-centered communication (PCC) and health self-efficacy. METHODS: Data for this study were derived from the Health Information National Trends Survey (HINTS 5, Cycle 4) collected from February 2020 to June 2020. This study only involved respondents who reported having been diagnosed with cancer (N=626). Descriptive analyses were performed, and the mediation models were tested using Model 6 from the SPSS macro PROCESS. Statistically significant relationships among PAEHR portal use, PCC, health self-efficacy, and physical and psychological health were examined using bootstrapping procedures. In this study, we referred to the regression coefficients generated by min-max normalization as percentage coefficients (bp). The 95% bootstrapped CIs were used with 10,000 resamplings. RESULTS: No positive direct associations between PAEHR portal use and cancer survivors' health outcomes were found. The results supported the indirect relationship between PAEHR portal use and cancer survivors' psychological health via (1) PCC (bp=0.029; β=.023, 95% CI .009-.054), and (2) PCC and health self-efficacy in sequence (bp=0.006; β=.005, 95% CI .002-.014). Besides, the indirect association between PAEHR portal use and cancer survivors' physical health (bp=0.006; β=.004, 95% CI .002-.018) via sequential mediators of PCC and health self-efficacy was also statistically acknowledged. CONCLUSIONS: This study offers empirical evidence about the significant role of PAEHR portals in delivering PCC, improving health self-efficacy, and ultimately contributing to cancer survivors' physical and psychological health.