This review focuses on third-generation tetracyclines, including tigecycline, eravacycline, and omadacycline, highlighting their mechanisms of action, resistance mechanisms, clinical pharmacology, spectrum of activity, established and potential indications, and non-antibiotic properties. Third-generation tetracyclines have been developed to address the challenges posed by resistance mechanisms such as efflux pumps and ribosomal protection proteins. They exhibit broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. The review details the pharmacokinetics and pharmacodynamics of each drug, emphasizing their effectiveness in treating various infections, such as community-acquired bacterial pneumonia (CABP) and acute bacterial skin and soft tissue infections (ABSSSI). Additionally, the review explores the potential of these drugs in treating infections caused by *Mycobacterium abscessus*, *Clostridioides difficile*, *Helicobacter pylori*, and urinary tract infections (UTIs). The synergistic benefits of combination therapy with other antibiotics are also discussed, particularly in treating severe infections caused by drug-resistant bacteria. Finally, the review highlights the non-antibiotic properties of these drugs, including their immunomodulatory effects and potential utility in managing certain malignancies.This review focuses on third-generation tetracyclines, including tigecycline, eravacycline, and omadacycline, highlighting their mechanisms of action, resistance mechanisms, clinical pharmacology, spectrum of activity, established and potential indications, and non-antibiotic properties. Third-generation tetracyclines have been developed to address the challenges posed by resistance mechanisms such as efflux pumps and ribosomal protection proteins. They exhibit broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. The review details the pharmacokinetics and pharmacodynamics of each drug, emphasizing their effectiveness in treating various infections, such as community-acquired bacterial pneumonia (CABP) and acute bacterial skin and soft tissue infections (ABSSSI). Additionally, the review explores the potential of these drugs in treating infections caused by *Mycobacterium abscessus*, *Clostridioides difficile*, *Helicobacter pylori*, and urinary tract infections (UTIs). The synergistic benefits of combination therapy with other antibiotics are also discussed, particularly in treating severe infections caused by drug-resistant bacteria. Finally, the review highlights the non-antibiotic properties of these drugs, including their immunomodulatory effects and potential utility in managing certain malignancies.