Background: Changes in colorectal cancer (CRC) care planning because of the coronavirus disease 2019 (COVID-19) pandemic and associated health-related quality of life (HRQoL) and well-being of patients with CRC are unknown. We report changes in CRC care and patient-reported outcomes including HRQoL, distress, and loneliness during the first wave of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: In April 2020, 4984 patients included in the nationwide Prospective Dutch Colorectal Cancer cohort were invited to complete a COVID-19-specific questionnaire, together with the validated European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30), De Jong Gierveld, and Hospital Anxiety and Depression Scale. Clinical data were obtained from the Netherlands Cancer Registry. Scores were compared with the year prior to COVID-19 and with an age- and sex-matched control population during COVID-19. Results: In total, 3247 (65.1%) patients responded between April and June 2020. Of the patients, 17% had canceled, postponed, or changed hospital visits to a telephone or video consult, and 5.3% had adjusted, postponed, or canceled treatment. Compared with controls, patients reported worse HRQoL but comparable distress and less social loneliness (patients = 21.2%; controls = 32.9%). Compared with pre-COVID-19, clinically meaningful deterioration of HRQoL was more prevalent in patients with changes in cancer care planning than in patients without changes. Prior to undergoing or currently undergoing treatment and infection worries were associated with lower HRQoL. Conclusions: CRC patients reported equal anxiety and depression but worse HRQoL than the control population. Changes in care planning were associated with deterioration of HRQoL and increased anxiety. In case of 1 or more risk factors, health-care specialists should discuss (mental) health status and possible support during future SARS-CoV-2 infection waves or comparable pandemics.