(1) Background: Patients’ satisfaction is based on the perceived health care services of individuals and is influenced by the level of care provided by the health care system. It is often based on the patients’ expectations of care and self-assessment of their experiences. The success of the Directly Observed Treatment Strategy (DOTS) also depends on the quality of health care provided at the Tuberculosis (TB) centers, which can be evaluated by satisfaction levels of the patients. (2) Methods: A tuberculosis facility-based cross-sectional study was carried out in Khyber Pakhtunkhwa province in Pakistan. A mixed-method approach was adopted for data collection. An interviewer-administered questionnaire was used for quantitative data collection from 269 patients who were registered at 11 TB centers and private clinics. Qualitative data were collected through 20 in-depth interviews, 15 key informant interviews, and a focus-group discussion. Binary logistic regression was employed for analysis of the data. (3) Results: More than half of the respondents (63.94%) were satisfied with the DOTS strategy. A high percentage of patients were dissatisfied with the availability of safe water, waiting space for patients, waiting time, privacy, and the processing of appointments. Results from the binary logistic regression showed that gender (AOR = 2.21, CI 1.07–4.58, p = 0.033), marital status (AOR = 3.12, CI 1.45–6.73, p = 0.004), employment status (AOR = 5.22, CI 2.44–1.21, p = 0.000), home ownership (AOR = 3.82, CI 1.94–7.54, p = 0.000), literacy (AOR = 2.17, CI 1.11–4.25, p = 0.023), households’ main occupation (AOR = 4.42, CI 1.12–17.38, p = 0.033), and level of income (AOR = 2.39, CI 1.13–5.04, p = 0.023) were the significant factors affecting satisfaction levels of the patients. (4) Conclusion: There are a number of areas that need improvement for successful TB eradication. Significant work is required to improve the quality of TB care in these specific areas from the patients’ perspective. For instance, female health workers’ involvement in the DOTS program can solve the problems of female respondents in rural areas. Improving the infrastructure facilities at the TB centers, allocation of doctors and nurses at the rural health centers would result in positive outcomes of the DOTS in Pakistan as well as in other developing countries.