Background: The global COVID-19 pandemic has drastically disrupted cancer care, potentially exacerbating patients’ distress levels. Patients with hematologic malignancies undergoing HSCT may be especially vulnerable to this pandemic stress given their well-documented heightened psychological distress and impaired quality of life (QOL). However, the association of the COVID-19 pandemic with distress and QOL is not well understood. Methods: We conducted a cross-sectional analysis of data from 205 patients with hematologic malignancies undergoing HSCT who were enrolled in a multi-site, randomized supportive care trial. We compared baseline pre-HSCT distress (depression, anxiety, and posttraumatic stress disorder [PTSD] symptoms) and QOL between participants enrolled pre-COVID-19 (i.e., 03/2019-01/2020) and during the COVID-19 pandemic (i.e., 03/2020-01/2021). We used the Hospital Anxiety & Depression Scale, PTSD Checklist, and Functional Assessment of Cancer Therapy-Bone Marrow Transplant to assess symptoms of depression, anxiety, and PTSD, as well as QOL respectively. We used regression models adjusting for age, gender, race, relationship status, and cancer diagnosis to examine the relationship between the period of enrollment and patient-reported distress and QOL. Results: Prior to COVID-19, 124 participants enrolled, and 81 participants enrolled during the COVID-19 pandemic. The two cohorts had similar baseline demographic and disease risk factors. Most participants were non-Hispanic (n = 185; 90.2%), White (n = 138; 86.3%), and female (n = 131; 64.5%) with a mean (SD) age of 54.9 (11.7) years. In multivariate regression models, enrollment during COVID-19 was not associated with pre-HSCT depression (B = 0.004; 95% CI, -0.02 to 0.03; p = 0.73), anxiety (B = 0.008; 95% CI, -0.01 to 0.03; p = 0.44), PTSD (B = 0.004; 95% CI, -0.004 to 0.01; p = 0.35) symptoms or QOL (B = -0.003; 95% CI, -0.02 to 0.01; p = 0.68). Conclusions: Contrary to the widespread notion that the COVID-19 pandemic has worsened distress in patients with cancer, we found no differences in pre-HSCT distress or QOL in patients with hematologic malignancies undergoing HSCT prior to or during the COVID-19 pandemic. Our findings highlight the need to comprehensively explore the multifactorial causes (e.g., illness experience, treatment burden) of distress and QOL deficits in HSCT recipients irrespective of the COVID-19 pandemic.