Cancer is the main cause of morbidity and mortality in every part of the world, regardless of human development. Cancer patients exhibit a wide range of signs and symptoms. Being diagnosed with cancer has a variety of consequences that can affect one's quality of life. The term "health-related quality of life" refers to a multidimensional concept that encompasses a person's whole health. The availability of data on the prevalence of poor quality of life among cancer patients in Ethiopia is critical in order to focus on early detection and enhance cancer treatment strategies. In Ethiopia, however, there is a scarcity of information. As a result, the aim of this study was to determine the pooled estimated prevalence of quality of life among cancer patients in Ethiopia. This systematic review and meta-analysis were searched through MEDLINE, Pub Med, Cochrane Library, and Google Scholar by using different search terms on the prevalence of health-related quality of life of cancer patients and Ethiopia. Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument was used for critical appraisal of studies. The analysis was done using STATA 14 software. The Cochran Q test and I2 test statistics were used to test the heterogeneity of studies. The funnel plot and Egger's test were used to show the publication bias. The pooled prevalence of health-related quality of life of cancer with a 95% confidence interval was presented using forest plots. A total of 12 studies with 3, 479 participants were included in this review and the overall pooled estimates mean score of health-related quality of life among cancer patients in Ethiopia was 57.91(44.55, 71.27, I2 = 98.8%, p≤0.001). Average monthly income (AOR:3.70;95%CI:1.31,6.10), Stage of cancer (AOR:4.92;95% CI:2.96,6.87), Physical functioning(AOR:4.11;95%CI:1.53,6.69), Social functioning(AOR:3.91;95% CI:1.68,6.14) were significantly associated with quality of life. Subgroup meta-analysis of health-related quality of life of cancer patients in Ethiopia done by region showed that a higher in Addis Ababa 83.64(78.69, 88.60), and lower in SNNP region16.22 (11.73, 20.71), and subgroup analysis done based on the type of cancer showed that higher prevalence of health-related quality of life among cancer patients was breast cancer 83.64(78.69, 88.60). This review showed that the overall health related quality of life was above an average. Furthermore, average monthly income, cancer stage, physical, and social functioning were all significant determinants in cancer patients' QOL.as a result, this review suggests that quality of life evaluation be incorporated into a patient's treatment routine, with a focus on linked components and domains, as it is a critical tool for avoiding and combating the effects of cancer and considerably improving overall health. In general, more research is needed to discover crucial determining elements utilizing more robust study designs.