Purpose: Previous research has systematically studied the effectiveness of Cognitive Behavioral Therapy (CBT)-based interventions in managing both mental and physical symptoms of chronic disease including depression, stress-related mental disorders (SMD), and chronic pain that are common causes of sick leave. However, a systematic review focusing on the effectiveness of CBT in facilitating RTW is lacking. This study compiles research on utilizing CBT-based interventions for helping employees on sick leave return to work. Methods: Randomized controlled trials (RCT) published between 1 January 1990 and 27 June 2022 were searched in MEDLINE, EMBASE, The Cochrane Library, Scopus, PsycINFO, Web of Science, and PubMed. The primary outcome variables included a return to work (RTW) measure and sickness absences. The secondary outcomes include psychological conditions (mental illness, stress, anxiety, and depression) and physical condition (working ability, fatigue, and physical function). Results: Thirty-four RCTs were included in the analysis. Fifteen RCTs with 1727 participants reported on sick leave. Results showed that participants who completed CBT intervention had reduced sick leave in days (mean reduction − 3.654; 95%CI − 5.253, − 2.046; p < 0.001) compared to the control group. Sixteen papers with 2298 participants reported that the intervention group RTW 1.5 days earlier (95%CI 1.019, 1.722; p < 0.05). CBT-based interventions were effective in managing fatigue, mental illness, and depression, and improving physical function while it showed no effects in managing stress, anxiety and working ability. Conclusions: The findings indicate that CBT-based interventions are effective in reducing the length of sick leave and facilitating the RTW of employees in the intervention group.