Abstract Background: Psychosocial care for oncology patients is now recognized as a critical aspect of care because it has a positive impact on patient outcomes. Various screening tools have been validated to objectively measure the levels of distress, such as the National Comprehensive Cancer Network distress thermometer. However, there is little evidence of its use in sub-Saharan Africa, where the cancer burden continues to increase. This study sought to evaluate the levels of psychological distress in patients with cancer and the impact of the COVID-19 pandemic. Methods: This was a single-center cross-sectional study among patients with a histological diagnosis of cancer attending the hemato-oncology and radio-oncology units at the Kenyatta National Hospital, a referral tertiary center. We used the National Comprehensive Cancer Network Distress Thermometer and Problem Checklist to define psychological distress, fear of COVID-19 scale, and Corona Anxiety Score to determine the level of fear and anxiety caused by COVID-19 given the study happened during the pandemic, and the Eastern Cooperative Oncology Group (ECOG) to assess the performance status. Results: Of the 361 patients, the median age was 54 years (interquartile range, 43–63), and most were female (70%). The leading cancer diagnosis was breast cancer (26%), followed by cervical cancer (24%), with most of the patients having advanced disease and 28% having ECOG 3. Most (80%) patients were able to continue with their treatment despite the COVID-19 pandemic; however, 71% had a high level of fear of COVID-19 but minimal anxiety symptoms based on Corona Anxiety Score. The mean distress thermometer score was 2.7 (SD, 2.6), with 30% having a high level of distress (4 or above). ECOG status was the only variable significantly associated with high levels of distress, with the strongest association observed in the highest ECOG status (ECOG 4: OR, 6.8 [95% CI, 2.8–16.6] P < .001). Transportation was the main problem in the practical domain (62%) while fears and worries in the emotional domain (46% and 49%, respectively), and pain (65%) were the main physical problems. Conclusions: One-third of patients experienced high levels of distress. These patients reported significant concerns, such as transportation, fears, worry, and pain, in the problem checklist. There is a need to incorporate screening for distress into our patient population to help identify these patients and institute appropriate interventions.