Hyperbaric oxygen therapy (HBOT) involves the administration of 100% oxygen at pressures greater than atmospheric levels, typically between 2 and 3 ATA, within a specialized chamber. While its historical roots trace back to the seventeenth century, HBOT has evolved into a scientifically validated therapeutic modality with applications across a diverse range of medical conditions. This chapter provides a comprehensive overview of the clinical evaluation process and contraindications associated with HBOT. Physiologically, HBOT leverages physical laws such as Henry’s and Boyle’s laws to significantly increase tissue oxygenation and modulate inflammatory and cellular repair pathways through the generation of reactive oxygen and nitrogen species. A thorough clinical evaluation, including assessment of the indication, pre-existing comorbidities, medication history, and chamber-specific limitations, is essential for safe and effective HBOT administration. Absolute contraindication includes untreated pneumothorax, while several relative contraindications—such as congestive heart failure, uncontrolled diabetes, recent thoracic surgery, and claustrophobia—require careful consideration. Standard pre-HBOT investigations include pulmonary function tests, chest X-ray, electrocardiogram, and tympanometry. Drug interactions, particularly with agents such as bleomycin and doxorubicin, must also be reviewed. Complications, although infrequent, may include barotrauma, oxygen toxicity (central nervous system and pulmonary), confinement anxiety, and reversible ocular changes. Given the expanding indications and therapeutic promise of HBOT, meticulous patient selection and protocol adherence are vital. This review underscores the importance of evidence-based evaluation to maximize clinical benefits while minimizing risks in HBOT practice.