BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder frequently requiring oxygen therapy to relieve symptoms and improve survival. In recent years, telehealth-supported interventions have emerged as promising strategies to optimize home oxygen therapy by promoting adherence, reducing hospitalizations, and enhancing health-related quality of life. However, evidence regarding their effectiveness remains inconsistent and equivocal, underscoring the need for further rigorous evaluation. OBJECTIVE: This study aimed to evaluate the clinical and cost-effectiveness of telehealth-supported home oxygen therapy on adherence, hospital readmission, and health-related quality of life in patients with COPD. METHODS: A comprehensive search was conducted across 6 databases (PubMed, Cochrane Central, Embase, Web of Science, PsycINFO, and CINAHL) up to October 1, 2024, and updated on April 28, 2025. Randomized controlled trials involving patients with COPD comparing telehealth-supported home oxygen therapy with usual care, and reporting outcomes on adherence, hospital readmissions, or health-related quality of life, were included. In addition, 2 reviewers independently screened the studies, extracted data, assessed the risk of bias using the Cochrane Risk of Bias 2 tool, and evaluated the certainty of evidence with the Grading of Recommendations Assessment, Development, and Evaluation approach. Meta-analyses and heterogeneity assessments were conducted using R software (R Core Team). Standardized mean differences with 95% CIs were calculated to evaluate the intervention effects under a random-effects model. RESULTS: In total, 8 studies comprising 1275 patients were included in the review. Telehealth-supported home oxygen therapy significantly reduced hospital readmissions (standardized mean difference [SMD]=-0.40, 95% CI -0.60 to -0.21) and improved health-related quality of life (SMD=0.49, 95% CI 0.25-0.73). No significant effect was observed on therapy adherence (SMD=0.19, 95% CI -0.76 to 1.14). Furthermore, 3 economic evaluations suggested that although telehealth interventions may incur higher initial costs, they are likely to result in long-term savings by reducing hospital admissions. Sensitivity analyses confirmed the robustness of the findings for hospital readmissions and health-related quality of life, for which the quality of evidence was rated as high, whereas the evidence for therapy adherence was rated as low. CONCLUSIONS: Telehealth-supported home oxygen therapy significantly reduces hospital admissions and improves health-related quality of life in patients with COPD, but does not significantly improve therapy adherence. Tailored interventions that consider patient demographics, combined with supportive policies, may further enhance clinical outcomes. Future research should incorporate economic evaluations to better inform policy decisions regarding the implementation of telehealth-supported home oxygen therapy. However, the overall certainty of evidence is limited by study-level risk of bias, variability in intervention designs, and imprecision of effect estimates, highlighting the need for further high-quality, standardized trials.