Aim To observe the plasma concentrations and pharmacokinetic-pharmacodynamic (PK-PD) profile of first-line antitubercular drugs in pulmonary tuberculosis (TB) patients with and without diabetes mellitus (DM). Methods Newly diagnosed pulmonary TB patients aged 18-60 with or without DM were included in the study. Group I (n = 20) included patients with TB, whereas Group II (n = 20) contained patients with TB and DM. After 2 weeks of therapy, plasma concentrations and other PK-PD parameters were determined. The improvement in clinical features, X-ray findings, sputum conversion and adverse drug reactions (ADRs) were measured after 2 months of ATT. Results Isoniazid displayed non-significantly higher plasma concentrations in diabetic patients, along with a significantly (P < 0.05) longer elimination half-life (t1/2). Rifampicin plasma concentration at 4, 8, and 12 h were significantly (P < 0.05) lower and it displayed significantly (P < 0.05) lower area under curves (AUC0-12 and AUC0-), shorter t1/2, higher clearance (Cl) and a lower AUC0-/MIC ratio in diabetic patients. Pyrazinamide and ethambutol showed non-significantly higher plasma concentrations, AUC0-12, AUC0-, and t1/2 in diabetic patients. The improvement in clinical features, X-ray findings, sputum conversion, and ADRs were comparable in both the groups. Conclusions The presence of DM in TB patients affects the PK-PD parameters of isoniazid, rifampicin, pyrazinamide and ethambutol variably in the Indian population. Studies in a larger number of patients are required to further elucidate the role of DM on the PK-PD profile of first-line antitubercular drugs and treatment outcomes in TB patients with concomitant DM.