Objective Approximately half of patients with cancer have comorbidities, such as adjustment disorder, major depressive disorder, and delirium. Radiotherapy can cause psychological problems, e.g., the fear of treatment and its side effects, anxiety, depression, and social isolation. Health-related quality of life (QoL) must be determined to evaluate the effectiveness of cancer treatment. We analyzed the clinical, psychological, and sociodemographic factors influencing the QoL of patients with cancer who were undergoing radiotherapy. Methods Twenty-six patients undergoing radiotherapy (10 male, 16 female) were included. Sociodemographic and clinical data were collected prior to radiotherapy. Psychosocial factors were assessed by self-reported questionnaires before, immediately after, and 3 months after radiotherapy. A multivariate regression analysis identified factors affecting QoL at each time point. Results Patients’ diagnoses were breast, cervical, prostate, endometrial, rectal, hypopharyngeal, laryngeal, liver, gallbladder, esophageal, ovarian, lung, and skin cancers. Before radiotherapy, better resilience was significantly associated with a higher QoL score (R2=0.199, p=0.033). Immediately after radiotherapy, financial difficulty was significantly associated with a lower QoL score (R2=0.274, p=0.010). Three months after radiotherapy, the presence of chronic disease (R2=0.398, p=0.002) and the severity of nausea and vomiting were significantly associated with a lower QoL score (R2=0.278, p=0.014). Conclusion Resilience, financial difficulty, the presence of chronic diseases, and the severity of nausea and vomiting significantly influenced the QoL of patients with cancer who were undergoing radiotherapy. Factors affecting QoL varied at each time point. Thus, patients with cancer should undergo regular mental health assessments, including assessments of QoL. Multidimensional (physical, psychological, and social) approaches and individualized time-based interventions are needed to improve the QoL of cancer patients undergoing radiotherapy.