More than 40% of adults in the United States suffer from obesity. Obesity is inextricably linked to many chronic illnesses like type‐2 diabetes mellitus, hypertension, hyperlipidemia, heart disease, sleep apnea, stroke, and cancers. When used in combination with lifestyle modifications, pharmacotherapy has a vital role in treating obesity and improves short‐term and long‐term outcomes. A growing number of physicians are now interested in obesity medicine, and many of them are seeking guidance on how to treat complex patients with co‐morbidities. This review provides a practical guide to the use of anti‐obesity medications across various obesity‐related comorbidities. It provides a general review of the currently approved anti‐obesity medications and effective combinations. It discusses the highlights of the major trials and recent studies assessing the benefits of anti‐obesity medications in comorbid conditions such as type‐2 diabetes mellitus, psychiatric disorders, cardiovascular diseases, hypertension, renal diseases, and liver diseases. This review briefly examines the aspects of recognizing and addressing iatrogenic weight gain; discusses the precautions and prescribing considerations of anti‐obesity medications, including side effects and possible dose adjustments in various comorbid conditions; and provides an expert opinion on an individualized choice of the best anti‐obesity medication.