Background: Pulmonary tuberculosis (TB) remains a major global health challenge, and the increasing prevalence of drug-resistant TB (DR-TB), including multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), poses a serious threat to effective disease control. Aim: To analyze the drug resistance patterns in pulmonary tuberculosis patients and assess the prevalence of mono-resistance, MDR-TB, and XDR-TB using sputum culture and drug susceptibility testing (DST). Methods: A cross-sectional observational study was conducted from January 2022 to December 2023 on 300 confirmed pulmonary TB patients at a tertiary care center. Samples were processed using ZiehlNeelsen staining, GeneXpert MTB/RIF, Line Probe Assay (LPA), and culture-based drug susceptibility testing for first- and second-line antiTB drugs. Demographic data, treatment history, and risk factors were also evaluated. Results: Out of 300 patients, 64 patients (21.3%) showed drug resistance. Rifampicin mono-resistance was seen in 10% of cases, isoniazid mono-resistance in 7.3%, MDR-TB in 6.6% (resistant to both INH and RIF), and XDR-TB in 2%. Prior TB treatment and noncompliance were found to be significant risk factors (p < 0.001). Resistance to fluoroquinolones and injectable second-line drugs was higher in previously treated patients. Conclusion: Drug-resistant TB is increasingly prevalent, especially among previously treated and non-compliant patients. Early detection by GeneXpert and LPA, strict adherence to treatment, and individualized therapy based on DST are essential to control DR-TB.