Background: Pakistan served as a host for more than 1.4 million Afghan refugees for more than 40 years. Access to health care is the most important issue faced by refugees, because they might be at a higher risk for certain diseases. This risk can be attributed to a lack of awareness of health care facilities, health beliefs, inadequate hygiene, cultural differences, and malnutrition. Health of individuals is closely associated with their quality of life. Quality of life over the whole lifespan is pivotal to overall life satisfaction. It includes physical wellbeing, mental health, education, occupation, income, personal safety, as well as (religious) freedom. Until now, the health status of Afghan refugees has never been comprehensively investigated in Pakistan. Therefore, an assessment in this regard is needed to explore their health-related quality of life, for securing their human right to health. Methods: A cross-sectional study has been designed to describe and explain the health-related quality of life of Afghan refugees in Pakistan. Multistage cluster sampling was applied for selection of study participants. The number of respondents from two regions in Pakistan was drawn through a proportionate sampling technique. A quantitative research method using pre-validated questionnaires was used for data collection. The questionnaire included items to assess well-being, mental health, health literacy, and factors affecting health and health care. Descriptive analysis was used, whereas inferential statistical tests (binary logistic regression model) was also performed. The study received ethically permission by the Advanced Studies and Research Board of the University of the Punjab, Lahore, Pakistan. Discussion: The assessment of Afghan refugee's quality of life in Pakistan should lead to recommendations disseminated to public and health care officials. This evidence is needed for policymaking related to adequate measures for improving health conditions of Afghan refugees in Pakistan.