Chronic dialysis patients have an increased risk of severe COVID-19 infection-related complications. The aim of this study was to quantify the impact of the COVID-19 pandemic on health-related quality of life (HRQoL) and physical activity levels of patients undertaking hemodialysis (HD). This was an observational study that compared data from two periods of time, before the COVID-19 pandemic vs pandemic. We used the Medical Outcomes Survey Short Form (SF-36) to measure the HRQoL and the Human Activity Profile (HAP) questionnaire was used to measure the physical activity. Data were analyzed with a mixed ordinal linear regression. A total of 27 eligible participants were interviewed during COVID-19 pandemic (median age 78 years). The linear regression model showed that the pandemic, after controlling for the covariates age, comorbidity, albumin, and hemoglobin, had a significant impact on the HRQoL. Physical function (−15.7) and social functioning subscales (−28.0) worsened (p = 0.001), and the physical component scale also showed a significant decrease (−3.6; p = 0.05). Time had a significant impact on the Human Activity Profile, with an average activity score diminished with the pandemic (−13.9; p = 0.003). The COVID-19 pandemic had a very negative impact on HRQoL and physical activity level of subjects undertaking hemodialysis. Interventions to improve HRQoL and activity levels of patients undertaking HD are recommended.