Monkeypox, a zoonotic disease caused by an orthopoxvirus, has evolved significantly since its initial detection in humans in 1970. This systematic review examines the changing epidemiology of human monkeypox, focusing on the number of confirmed, probable, and possible cases, age at presentation, mortality, and geographical spread. The review identified 48 peer-reviewed articles and 18 grey literature sources. Since the 1970s, the number of human monkeypox cases has increased, with the most significant increases occurring in the Democratic Republic of the Congo (DRC). The median age at presentation has increased from 4 years in the 1970s to 21 years in 2010-2019. The overall case fatality rate is 8.7%, with a significant difference between clades—Central African 10.6% (95% CI: 8.4%–13.3%) vs. West African 3.6% (95% CI: 1.7%–6.8%). Since 2003, import- and travel-related spread outside Africa has occasionally resulted in outbreaks. Interactions/activities with infected animals or individuals are risk behaviors associated with acquiring monkeypox. The review highlights the escalation of monkeypox cases, especially in the highly endemic DRC, the spread to other countries, and the growing median age from young children to young adults. These findings may be related to the cessation of smallpox vaccination, which provided some cross-protection against monkeypox, leading to increased human-to-human transmission. The appearance of outbreaks beyond Africa underscores the global relevance of the disease. Increased surveillance and detection of monkeypox cases are essential tools for understanding the continuously changing epidemiology of this resurging disease.Monkeypox, a zoonotic disease caused by an orthopoxvirus, has evolved significantly since its initial detection in humans in 1970. This systematic review examines the changing epidemiology of human monkeypox, focusing on the number of confirmed, probable, and possible cases, age at presentation, mortality, and geographical spread. The review identified 48 peer-reviewed articles and 18 grey literature sources. Since the 1970s, the number of human monkeypox cases has increased, with the most significant increases occurring in the Democratic Republic of the Congo (DRC). The median age at presentation has increased from 4 years in the 1970s to 21 years in 2010-2019. The overall case fatality rate is 8.7%, with a significant difference between clades—Central African 10.6% (95% CI: 8.4%–13.3%) vs. West African 3.6% (95% CI: 1.7%–6.8%). Since 2003, import- and travel-related spread outside Africa has occasionally resulted in outbreaks. Interactions/activities with infected animals or individuals are risk behaviors associated with acquiring monkeypox. The review highlights the escalation of monkeypox cases, especially in the highly endemic DRC, the spread to other countries, and the growing median age from young children to young adults. These findings may be related to the cessation of smallpox vaccination, which provided some cross-protection against monkeypox, leading to increased human-to-human transmission. The appearance of outbreaks beyond Africa underscores the global relevance of the disease. Increased surveillance and detection of monkeypox cases are essential tools for understanding the continuously changing epidemiology of this resurging disease.