Lower extremity amputations and diabetic foot-related complications in the Caribbean population have been previously reported. However, there is a lack of evidence that assess the quality of life experienced in such amputees. This study aimed to determine the health-related quality of life (HRQoL) in patients after a major lower limb amputation. Data collection was performed for all major lower limb amputations undertaken at a tertiary care institution in Trinidad and Tobago, between January 2012 to December 2016. The quality of life for patients who were accessible, alive, and willing to participate was assessed using the EuroQol 5D-5L tool. Statistical analysis was performed using the Mann-Whitney U and Kruskal-Wallis tests comparing medians across various subgroups. A total of 134 individuals were still alive and willing to participate in the study. The average EQ-5D-5L index value for the cohort was (0.598), which was significantly lower compared to EQ-5D-5L population norms for Trinidad and Tobago p < 0.05. Statistically significant differences were also seen in median EQ-5D-5L index value for patients who ambulated with a prosthesis (0.787) compared to those who used another device for mobilization (0.656), p < 0.05, and to those patients who did not ambulate (0.195), p < 0.05. A comparable Quality of life was seen between the level of amputation (transtibial versus transfemoral) and gender (males versus females), p-values were 0.21 and 1.0, respectively. Overall quality of life after major amputation, as well as independent mobilization with a prosthesis, continues to be problematic in the Caribbean population. Factors adversely related to the quality of life post major amputation include increasing age, problems related to mobility, and non-ambulatory patients.