Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care, with increasing data demonstrating improved survival outcomes using ICIs among patients with advanced gastroesophageal cancer (aGEC). ICIs are also associated with a lower incidence of grade ≥3 adverse effects (AEs) compared to chemotherapy (CT), suggesting that ICIs may have favorable effects on health-related quality of life (HRQoL). This meta-analysis sought to evaluate the effects of ICIs on the HRQoL of patients with aGEC. Methods: An online bibliographic search was conducted on Medline via PubMed using MeSH-based terms to retrieve randomized controlled trials (RCTs) that evaluated the effects of ICIs on HRQoL in patients with aGEC. We included RCTs that incorporated ICIs as part of the intervention arm either as monotherapy (second-line) or as a combination therapy (first-line) with another ICI or CT. We combined the HRQoL measures into a meta-analysis using standard random effects models, from which estimates of the average mean difference (MD) were obtained with 95% confidence intervals. We assessed heterogeneity of the study outcomes using the Q and I² statistics. Results: 11 phase-3 RCTs were included, with a mean enrollment of 820 patients. Most (n=X) of the RCTs had ICI plus CT combination in the intervention arm, three had ICIs as monotherapy, and one had doublet ICI therapy in the intervention arm. All RCTs had CT for the control arm. Collectively, trials reported 37 HRQoL measures using 5 different HRQoL tools. The pooled analysis favored the intervention over the control arm in terms of Functional Assessment of Cancer Therapy-Esophageal (FACT-E) scores [MD 2.7 (95% CI 0.1 to 5.3), p<0.05]. In a subgroup analysis of 8 RCTs comparing combination therapy with ICIs plus CT versus CT alone, the effect estimates favored the ICI arm regarding the FACT-E [MD 2.7 (95% CI 0.1 to 5.3), p<0.05] and the EORTC QLQ-OES18 pain scale [MD -2.2 (95% CI -4.3 to -0.2), p<0.05]. We found no statistically significant differences in HRQoL scales in subgroup analysis of ICI monotherapy versus CT. Conclusions: In this meta-analysis, we found that the inclusion of ICIs as first-line treatment for aGECs yielded better HRQoL outcomes than CT. Further research on the impact of ICIs on HRQoL is needed, yet with increasing evidence that ICIs improve survival outcomes in patients with aGEC, these corresponding benefits with HRQoL are encouraging.