The COVID-19 pandemic, starting in 2020, has presented a major challenge in terms of early diagnosis and the subsequent containment and management of severe cases. The spread of viruses such as monkeypox in non-endemic countries is now creating new difficulties for healthcare professionals. Proper case definition and clinical examination are crucial for the early identification of suspected cases. For this reason, we performed a review of the literature in order to report the first signs, which are useful for healthcare providers for early case identification. Since 2022 to date, 86,930 laboratory-confirmed cases and 1051 probable cases have been reported worldwide, and of these, 116 were fatal cases and, for the first time, most of the cases were registered in countries that have not historically reported monkeypox and that lack direct or immediate epidemiological links to areas of West or Central Africa where the disease is endemic. Patients with Monkeypox experience prodromal symptoms, such as fever, fatigue, headache, muscle aches, and a rash after an incubation period of 5–21 days. The disease is usually self-limiting within 2–4 weeks but can lead to complications, such as pneumonia, encephalitis, kidney injury, and myocarditis in children, pregnant individuals, and those with weakened immune systems. The case–fatality ratio is between 1 and 10%. Today, prevention campaigns and the control of human monkeypox are the best weapons to prevent infection and stop transmission. Prevention strategies, such as avoiding contact with sick or dead animals, and the proper preparation of all foods containing animal meat or parts, should be adopted. Furthermore, close contact with infected people or contaminated materials should be avoided to prevent human-to-human transmission.