Objective Health-related quality of life (HRQoL) is a critical determinant to assess the severity of chronic diseases like diabetes mellitus. It has a close association with complications, comorbidities, and medical aid. This study aimed to estimate the prevalence of medical comorbidities and determine the relationship between comorbidities and HRQoL among type 2 diabetic patients of southern Bangladesh. Method This study was a cross-sectional study conducted through face to face interviews using a pre-tested structured questionnaire and by reviewing patient’s health records with prior written consent. The study was conducted on 2,136 patients with type 2 diabetes attending five hospitals of Chattogram, Bangladesh, during the tenure of November 2018 to July 2019. Quality of life was measured using the widely-used index of EQ-5D that considers 243 different health states and uses a scale in which 0 indicates a health state equivalent to death and 1 indicates perfect health status. The five dimensions of the quality index included mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Results Patients with three comorbidities and with four or more comorbidities had a higher probability of reporting “extreme problem” or “some problem” in all five dimensions of the EQ-5D index compared with those without comorbidity (Odds ratio: mobility, 3.99 [2.72–5.87], 6.22 [3.80–10.19]; usual activity, 2.67 [1.76–4.06], 5.43 [3.28–8.98]; self-care, 2.60 [1.65–4.10], 3.95 [2.33–6.69]; pain or discomfort, 2.22 [1.48–3.33], 3.44 [1.83–6.45]; anxiety or depression, 1.75 [1.07–2.88], 2.45 [1.19–5.04]). The number of comorbidities had a negative impact on quality of life. Conclusion Prevalent comorbidities were found to be the significant underlying cause of declined HRQoL. To raise diabetes awareness and for better disease management, the exposition of comorbidities in regards to HRQoL of people with diabetes should be considered for type 2 diabetes management schemas.