Weaning from mechanical ventilation after cardiac surgery is a dynamic, multifaceted process that extends beyond respiratory function alone. While most patients experience timely extubation, others face delayed or failed weaning due to the complex interplay of perioperative factors. This review provides an integrative overview of the weaning process, beginning with key definitions and classifications specific to the cardiothoracic population. It then explores the underlying pathophysiological determinants, including cardiopulmonary interactions, impaired lung mechanics, right heart failure, and altered intrathoracic pressure dynamics. Surgical strategies and anesthesia management also critically influence weaning trajectories, with evidence suggesting a variable impact based on surgical approach, cardiopulmonary bypass use, and intraoperative ventilation settings. The role of spontaneous breathing trials and protocolized weaning is reviewed, highlighting their applicability and limitations in this unique setting. An extensive analysis of monitoring tools—such as esophageal manometry, diaphragm ultrasound, and electrical impedance tomography—follows, emphasizing their role in phenotyping and individualizing care. Sedation, analgesia, and delirium management are discussed as key drivers of liberation success, along with the impact of preexisting and acquired neuromuscular dysfunction. Nutritional status, muscle wasting, and sarcopenia are also addressed as systemic barriers to ventilator liberation. Importantly, this review considers the long-term consequences of weaning failure, including functional disability and persistent neurocognitive impairment. We propose an integrated, multimodal framework for assessing readiness to wean and underscore the importance of postextubation trajectories. Future research should focus on the development of digital dashboards, predictive indices, and personalized protocols to optimize ventilator liberation and improve long-term outcomes in cardiac surgery patients.