Pharmaceutical companies have been known to pose stress and mental harassment on medical sales representatives (MSRs) in-order to increase pharmaceutical sales. This cross sectional descriptive study, conducted during November and December 2014 in the Lahore and Bahawalpur districts of Punjab, Pakistan, evaluates the Health-Related Quality of Life (HRQoL) and extent of depression among MSRs in Pakistan. The significant predictors of HRQoL and depression among the MSRs were also determined. Using a convenience sampling technique, all consenting MSRs (N = 318) of pharmaceutical companies were asked to self-complete the Short Form-36 (SF-36v2) Health Survey and Stanford Personal Health Questionnaire (PHQ-8). The standard scoring scheme for the SF36v2 and PHQ-8 questionnaires was used. The PHQ-8 scores showed that 16.4 % (n = 52) and 2.5 % of respondents were suffering from major depression and severe major depression, respectively. Being depressed and having difficulty in achieving sales targets were the factors independently associated with lower physical health. Similarly, depression, insufficient time for the family and monthly income less than 36,000 Pakistan Rupees were significant predictors of lower mental health. The factors associated with depression included insufficient time for the family and unsatisfactory behavior of the managers. Compromised mental health and the prevalence of depression among the MSRs suggest pharmaceutical companies need to devise health management strategies and interventions to ensure effective prevention and management of mental health problems among Pakistani MSRs.