<p>Tuberculosis stands as one of the most lethal illnesses, responsible for a significant number of fatalities annually. Consequently, eradicating tuberculosis stands as a primary goal for researchers worldwide. Multitarget drug therapy holds considerable importance in addressing various deadly diseases, including tuberculosis, cancer, and diabetes. This review article offers insights into the historical background, human tuberculosis mechanisms, diverse receptor types, combination therapy, clinical stages of various anti-TB medications, and their resistance. It outlines drugs targeting different receptors, with some still in the lead identification phase but demonstrating notable efficacy against tuberculosis. The article also addresses the causes and types of drug resistance, such as patient noncompliance, intrinsic and extrinsic factors, and resistance related to tuberculosis strains. It lists current drugs undergoing clinical trials, including GSK070, CPZEN-45, Q203, TBAJ-587, and TBAJ-876, among others. Additionally, it highlights combination drug studies that have shown promise, such as the pairing of Cephalosporin with Beta-lactam drugs and clavulanate to enhance Rifampicin’s activity against TB, as well as the combination of Meropenam-Clavulanate and Cotrimoxazole. Furthermore, the article discusses the reported antimicrobial, analgesic, anti-inflammatory, antihypertensive, and antitumor properties of thiophene-based compounds.</p>