This study aims to assess tuberculosis (TB) patients' health-related quality of life (HRQoL) and to determine the relationship between HRQoL and the socioeconomic and health characteristics of patients. A mixed-method approach of explanatory sequential design is used in this study. Data were collected at 11 TB centers and two private clinics in Khyber Pakhtunkhwa, Pakistan. Quantitative data were collected through a standardized questionnaire (SF-36) of RAND organization from 269 pulmonary TB patients. Qualitative data were collected through 20 in-depth interviews, 15 Key Informant interviews, and a focus group discussion. The maximum score of SF-36 is 100, however, different aspects of HRQoL indicated that patients scored lowest in the role limitation physical (10.3) and emotional (11.2) categories, while the highest remained in the mental health (45.3) category. Patients of higher age, being female, low household income, and comorbidity decreased the HRQoL. Qualitative findings show that TB affected the patients' social functioning, vitality, and emotions. Moreover, poverty and low income, people living in Kacha Houses, family support, and the hate from family members and community are related to low HRQoL. In summary, TB has affected the Patients' HRQoL. TB program managers should pay attention to the nonmedication aspects of TB management. Financial support should be extended TB patients. This study calls for the urgent attention of the National Tuberculosis Program and policymakers, for an increased focus on patients' welfare programs.