Purpose <p>This study used a mobile-based assessment tool to evaluate the dynamics of distress and quality of life (QoL) in patients with esophageal, head and neck, and rectal cancers undergoing radiation therapy (RT).</p> Methods <p>A prospective cohort study was conducted between November 2022 and July 2023 and included 100 patients who had completed assessments at pre-RT, weeks 2, 4, and 6 of RT, and 1&#xa0;month post-treatment. The National Comprehensive Cancer Network Distress Thermometer and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire were used.</p> Results <p>All patients showed a 100% response rate to the mobile-based assessment at pre-RT, week 6, and post-treatment, with a 95% response rate at weeks 2 and 4 of RT. Of the 100 patients, 33% experienced marked distress pre-RT, with distress levels peaking at 67% at weeks 2 and 4. More than 50% of the patients reported experiencing sleep disturbance, fatigue, worry, or anxiety post-treatment. Their QoL dropped significantly during treatment from levels in weeks 2 and 4 and returned to pre-treatment levels post-RT. Higher distress was consistently correlated with poorer QoL. Emotional and physical issues such as pain and sleep disturbance were significantly associated with poor QoL pre- and post-RT.</p> Conclusion <p>RT was associated with increased distress and a temporary reduction in QoL. Key factors including sleep problems, fatigue, and emotional distress require targeted interventions to improve patient outcomes. Mobile technology use has proven effective in tracking distress and QoL in patients with cancer undergoing RT.</p>