Taiwan had the second highest number globally of end-stage renal disease patients undergoing treatment in 2018. A meta-analysis of Chen et al. (2021) showed the incidence and mortality rates of COVID-19 were 7.7% and 22.4%, respectively. Few studies have explored the effects of patients’ self-participation and perceptions of hemodialysis on their quality of life. This study aimed to explore the factors related to hemodialysis patients’ quality of life during the COVID-19 pandemic. This study was a descriptive correlational study. Patients were recruited (n = 298) from the hemodialysis unit of a medical center in northern Taiwan. Variables included patients’ sociodemographic, psychological, spiritual, and clinical characteristics (i.e., perceived health level, comorbidities, hemodialysis duration, weekly frequency, transportation, and accompaniment during hemodialysis), perceptions of hemodialysis, self-participation in hemodialysis, and health-related quality of life (KDQOL-36 scale). Data were analyzed using descriptive and bivariate and multivariate linear regression. Multivariate linear regression, after adjusting for covariates, showed that anxiety, self-perceived health status, two vs. four comorbidities, and self-participation in hemodialysis were significantly associated with quality of life. The overall model was significant and accounted for 52.2% (R2 = 0.522) of the variance in quality of life during hemodialysis (adjusted R2 = 0.480). In conclusion, the quality of life of hemodialysis patients with mild, moderate, or severe anxiety was poorer, whereas that of patients with fewer comorbidities, higher self-perceived health status, and higher self-participation in hemodialysis was better.