Epidemics and outbreaks caused by the dengue virus pose risks to populations and have high mortality rates, causing burdens and economic costs worldwide. Brazil recently experienced an explosive increase in the number of dengue cases and fatalities. Dengue is an acute febrile illness that can progress to severe forms. It affects more than 100 countries, presenting ongoing challenges in Brazil and globally since its identification. Other conditions may be overlooked or mistaken for dengue. The most important differential diagnoses are other infectious diseases and rheumatological, hematological, gastroenterological, and neurological disorders. In this article, we discuss the primary differential diagnoses of dengue and offer a literature review highlighting the key clinical differences among clinicians. This review emphasizes the critical importance of differentiating dengue fever from infectious diseases such as meningococcemia and malaria and autoimmune and rheumatological conditions such as systemic lupus erythematosus to ensure timely and appropriate management.