Aim: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) assesses the health-related quality of life of patients in cancer trials. There are currently no minimally important difference (MID) guidelines for the EORTC QLQ-C30 for colorectal cancer (CRC). This study aims to estimate MIDs for the EORTC QLQ-C30 scales in patients with advanced CRC treated with chemotherapy and enrolled in clinical trials. Method: The data were obtained from three published EORTC trials that treated CRC patients using chemotherapy. Potential anchors were selected from clinical variables based on their correlation with EORTC QLQ-C30 scales. Anchor-based MIDs for within-group change and between-group change were estimated via the mean change method and linear regression, respectively, and summarized using weighted correlation. Distribution-based MIDs were also examined. Results: Anchor-based MIDs were determined for deterioration in 8 of the 14 EORTC QLQ-C30 scales and in 9 scales for improvement, and varied by scale, direction of change and anchor. MIDs for improvement (deterioration) ranged from 6 to 18 (−11 to −5) points for within-group change and 5 to 15 (−10 to −4) for between-group change. Summarized MIDs (in absolute values) per scale mostly ranged from 5 to 10 points. Conclusions: These findings have clinical relevance for the interpretation of treatment efficacy and the design of clinical trials by informing sample size requirements.