Purpose: Gastrointestinal (GI) cancer has emerged as a major health problem. Cancer patients receive informal care from their families beyond formal care. There has been little evidence showing how the health-related quality of life (HRQOL) of the caregivers differs from that of the GI patients in Malaysia. A cross-sectional study was conducted in three referral hospitals in Malaysia. The objectives of this study were to determine the HRQOL of GI cancer patients and their family caregivers, and assess whether there is any significant relationship between the demographic factors, and the physical component summary (PCS) and mental component summary (MCS) scores for patients and caregivers. Methods: A total of 323 dyads of GI cancer patients and their caregivers completed the Medical Outcomes Study 12-item Short Form (MOS SF-12) questionnaire to measure their HRQOL during face-to-face interviews. The analyses were performed using SF-12 scoring software to compute PCS and MCS scores (HRQOL parameters). The independent t test, one-way ANOVA, and the Pearson correlation test were conducted to determine the demographic factors related to the HRQOL of the dyads. Results: The caregivers had higher scores in all domains for the SF-12 than the patients. There were significant differences found in the MCS scores of the patients according to ethnicity, origin of cancer, duration of cancer, and surgery. None of these factors had a significant relationship with the caregivers’ HRQOL. Conclusion: Caregivers had better HRQOL than cancer patients. Early intervention for cancer patients in the form of counselling and personalised pain management may enhance the HRQOL of patients.