Background Maintenance hemodialysis (MHD) patients are particularly vulnerable to coronavirus disease 2019 (COVID-19), a viral disease that may cause interstitial pneumonia, impaired alveolar gas exchange and hypoxemia. We ascertained the time course of intradialytic arterial oxygen saturation (SaO2) in MHD patients between 4 weeks pre-diagnosis and the week post-diagnosis of COVID-19. Methods We conducted a quality improvement project in confirmed COVID-19 in-center MHD patients from 11 dialysis facilities. In patients with an arterio-venous access, SaO2 was measured 1×/min during dialysis using the Crit-Line monitor (Fresenius Medical Care, Waltham, MA, USA). We extracted demographic, clinical, treatment and laboratory data, and COVID-19-related symptoms from the patients’ electronic health records. Results Intradialytic SaO2 was available in 52 patients (29 males; mean ± standard deviation age 66.5 ± 15.7 years) contributing 338 HD treatments. Mean time between onset of symptoms indicative of COVID-19 and diagnosis was 1.1 days (median 0; range 0–9). Prior to COVID-19 diagnosis the rate of HD treatments with hypoxemia, defined as treatment-level average SaO2 <90%, increased from 2.8% (2–4 weeks pre-diagnosis) to 12.2% (1 week) and 20.7% (3 days pre-diagnosis). Intradialytic O2 supplementation increased sharply post-diagnosis. Eleven patients died from COVID-19 within 5 weeks. Compared with patients who recovered from COVID-19, demised patients showed a more pronounced decline in SaO2 prior to COVID-19 diagnosis. Conclusions In HD patients, hypoxemia may precede the onset of clinical symptoms and the diagnosis of COVID-19. A steep decline of SaO2 is associated with poor patient outcomes. Measurements of SaO2 may aid the pre-symptomatic identification of patients with COVID-19.