PurposeThe purpose of this study was to investigate the relationships between distress, psychological adjustment, and quality of life in patients with colon cancer. MethodThis study employed a cross-sectional design and included 104 colon cancer patients treated at AHEPA Hospital, Thessaloniki, Greece. The assessment tools used encompassed the Distress Thermometer, MINI-MAC scale, and FACT-C to evaluate distress, psychological adjustment, and quality of life. Statistical analysis, conducted in SPSS software, encompassed correlation tests and linear regression to explore the interplay between these variables in colon cancer patients. ResultsCorrelation tests revealed that patients’ quality of life is positively correlated with a fighting spirit (r = 0.719, p < 0.001), cognitive avoidance (r = 0.634, p < 0.001), and fatalism (r = 0.518, p < 0.001), and negatively with helplessness and hopelessness (r = −0.756, p < 0.001), and anxious preoccupation (r = −0.679, p < 0.001). OLS regression findings verified these results partially for a significance level of 5% but indicated no statistically significant effect of cognitive avoidance and fatalism on quality of life, which was further found unaffected by total distress. ConclusionsThe intricate links between quality of life, distress, and psychological adjustment in colon cancer patients call for deeper investigation. A personalized approach in psycho-oncology care is essential for comprehensive treatment. These findings highlight the significance of addressing the psychological and emotional needs of colon cancer patients, as observed in the study's results.