AbstractPositive adjustment to chronic diseases reduces psychiatric comorbidity and enhances quality of life. Very little is known about the benefit of internet-based and mobile-based Cognitive Behavioral Therapy (IM-CBT) on physical outcomes and its reciprocal interactions with psychiatric outcomes, the active therapeutic elements, and effect moderators among people with major chronic medical conditions. In this systematic review and meta-analysis (PROSPERO: CRD42022265738), CINAHL of Systematic Reviews, MEDLINE, PsycINFO, PubMed, Web of Science are systematically searched up to 1 June 2022, for randomized controlled trials (RCTs) comparing IM-CBT against non-CBT control condition(s) among people with chronic disease(s). Primary outcomes include improvements in psychiatric symptoms (depressive, anxiety, PTSD symptoms, general psychological distress) from baseline to post-intervention and follow-ups. Secondary outcomes include improvements in physical distress (physical symptoms, functional impairment, self-rated ill health, objective physiological dysfunction). Among 44 RCTs (5077 patients with seven different chronic diseases), IM-CBT improves depressive symptoms, anxiety symptoms, and general psychological distress at post-intervention and across follow-ups, and improves physical distress and functional impairment at post-intervention. Preliminary evidence suggests that behavioral modification and problem-solving could be necessary components to reduce psychiatric symptoms in IM-CBT, whereas cognitive restructuring, psychoeducation, and mindfulness elements relate to reduced physical distress. IM-CBT shows stronger benefits in chronic pain, cancer, arthritis, and cardiovascular disease, relative to other conditions. Changes in psychiatric symptoms and physical distress prospectively predict each other over time. IM-CBT is an effective intervention for comprehensive symptom management among people with chronic diseases.