Abstract Objectives The aim of this study was to assess the knowledge and attitudes towards monkeypox infection among physicians, a frontline healthcare worker group, in Saudi Arabia. Methods A cross-sectional, online survey assessing knowledge and attitudes towards monkeypox infection on multiple-item scales was sent to physicians in Saudi Arabia. The associations between independent factors and either knowledge or attitude were assessed. Results The final analysis included 398 participants. Approximately 57% of the participants were under 30 years old, and 56.8% were male. Only 18.6% of the surveyed participants had ever received information about monkeypox in their medical education. A substantial proportion of assessed physicians lack knowledge regarding the endemicity of monkeypox, its transmission, clinical differences with smallpox, chickenpox, and influenza, as well as the clinical evolution and the main associated findings. In addition, there is a significant knowledge gap between the therapeutic management of monkeypox and its vaccination. Such poor knowledge is influenced by various factors. Conclusions Physicians' knowledge and attitudes regarding monkeypox infection are inadequate. Training and knowledge assessment is important, as demonstrated by previous epidemics and pandemics such as Zika and COVID-19, especially when studies show significant improvement in related and specific knowledge.