The role of colchicine for the prevention of postoperative atrial fibrillation (POAF) after cardiothoracic surgery is not well-established. We aimed to evaluate its potential in preventing POAF using data from randomized controlled trials (RCTs). A literature search was performed to identify studies reporting POAF as an outcome after cardiac or thoracic surgery in adult patients randomized to either colchicine or placebo. Primary outcome measured was incidence of POAF. Secondary outcomes included gastrointestinal (GI) adverse effects, sepsis, and length of stay. Subgroup analyses based on treatment durations and type of surgery were also performed, as well as regression analyses to control for covariates. We identified a total of 5377 patients (colchicine = 2,689, placebo = 2688). Although colchicine use was associated with a significantly reduced risk of POAF, risk of GI adverse effects were significantly higher. The rates of infection and length of stay were similar across the groups. Subgroup analyses showed that colchicine was effective for POAF prevention in cardiac surgery, but not in thoracic surgery. Prevention of POAF and incidence of GI adverse effects were similar in short-term and long-term colchicine treatment. Colchicine significantly reduces the incidence of POAF in patients undergoing cardiac surgery, but not in thoracic surgery.