The aim of the present study was to evaluate the quality of life (QoL) of oral submucous fibrosis (OSMF) patients using the World Health Organization Quality of Life-BREF (WHOQOL-BREF) questionnaire. This cross-sectional study was conducted at the Department of Oral and Maxillofacial Surgery, Liaquat University of Medical and Health Sciences (LUMHS), Jamshoro. We used the consecutive sampling technique to recruit patients who were clinically diagnosed with OSMF (n = 112). Data were collected using the WHOQOL-BREF questionnaire, which contains a total of 26 questions. The first two questions, related to overall QoL and overall health status, were evaluated separately. The remaining questions (3-26), which represented four domains-physical, psychological, social, and environmental health-were evaluated separately. Patients were asked questions in their native language (Urdu). The relationship between these four domains of life was evaluated with gender, age categories, functional staging, and habit duration using the independent t-test to determine statistical significance. Cronbach's Alpha was used to assess the reliability of the WHOQOL-BREF domains. The overall QoL of the OSMF patients was considerably poor, and the majority of the patients were unsatisfied with their oral health status. The age variable significantly affected the scores of all domains except for social relationships, whereas habit duration and functional staging of OSMF did not significantly affect the scores of all domains. The domains of the WHOQOL-BREF questionnaire (translated into the Urdu language) showed good reliability, except for social relationships.