Human monkeypox is an emerging viral zoonotic infectious disease caused by a DNA virus that belongs to the Orthopoxvirus genus. Knowledge of monkeypox, high index and sound clinical judgement particularly amongst medical doctors is critical to responding to monkeypox effectively. Previous studies have shown poor knowledge of monkeypox infection amongst doctors. This study aims to assess doctors’ knowledge of monkeypox and their confidence in diagnosing monkeypox prior to laboratory confirmation. A cross-sectional online survey containing 28-item scale and explanatory variables were used to assess respondents’ knowledge, confidence and risk perception on monkeypox. The participants were reached with online Google form posted on the Nigerian Medical Association group WhatsApp, Cross River State. The questionnaires were structured closed-ended and were self-administered to collect quantitative data. A total of 164 medical doctors working in Cross River State participated. Only 38 (23.2%) of them had good knowledge of monkeypox, using a > 60% cutoff point for good knowledge. Seventy-two percent (72%) displayed confidence to clinically diagnose monkeypox in their daily clinic runs. There was statistically significant relationship between knowledge category and medical sub-specialties (X2 =6.98; p=0.03). We conclude that knowledge of monkeypox amongst medical doctors practicing in Cross River State, Nigeria is currently low, though confidence to diagnose it is high, this confidence should be backed with sound medical knowledge to improve doctors’ capacity to respond to the emerging monkeypox infection.