Patient's quality of life should be included in clinical decision making regarding the administration of adjuvant chemotherapy (ACT) in stage II/III colon cancer. Therefore, quality of life, summarized as health utility (HU), was evaluated for patients treated with and without ACT. Furthermore, the role of chemotherapy–induced peripheral neuropathy (CIPN) on HU was evaluated. Patients diagnosed with stage II/III colon cancer between 2011 and 2019 and participating in the Prospective Dutch ColoRectal Cancer cohort were included (n = 914). HU scores were assessed with the EQ-5D-5L at baseline, 3, 6, 12, 18, and 24 months. Patients treated with ACT received mainly capecitabine and oxaliplatin (57%) or capecitabine monotherapy (40%) (average duration: 3.5 months). HU 3 to 18 months after diagnosis (potential ACT period + 12 months follow-up) was compared between patients treated with and without ACT using a mixed model adjusted for age, sex and education level. Subsequently, the CIPN sensory, motor and autonomy scales, measured using the EORTC QLQ-CIPN20, were independently included in the model to evaluate the impact of neuropathy. Using a mixed model, a significant difference of −0.039 (95% confidence interval: −0.062; −0.015) in HU was found between patients treated with and without ACT. Including the CIPN sensory, motor and autonomy scales decreased the difference with 0.019, 0.015 and 0.02, respectively. HU 3 to 18 months after diagnosis is significantly lower in patients treated with ACT vs without ACT. This difference is on the boundary of clinical relevance and appears to be partly related to the sensory and motor neuropathy-related side effects of ACT.