Background & Objective: Acute rheumatic fever (ARF) is a major public health issue among children with increased morbidity and mortality. This study aimed to explore clinical medical students' perceptions and awareness of ARF and the potential for developing a future vaccine, as well as to document the factors associated with these views. Materials & Methods: This cross-sectional study was conducted in two medical schools in the Enugu metropolis from July 2024 to October 2024. The study enrolled 341 clinical medical students from two medical schools in Southeast Nigeria. Data were collected using a validated interviewer-administered questionnaire. The questionnaire included 11 variables to assess the students' ARF knowledge. The maximum obtainable mark for each respondent was 29. Knowledge of ARF vaccination was assessed using eight variables. Results: Most respondents (93.0 %) demonstrated awareness of ARF. Just over half (50.7 %) recognized sore throat as a symptom of ARF. Fifty-one point-three per cent of respondents demonstrated good knowledge of ARF. Most respondents (86.8%) knew vaccination could be an effective preventive measure against the disease if available. Fourth-year respondents were five times less likely to possess good knowledge of ARF compared to their sixth-year counterparts, with an Adjusted Odds Ratio (AOR) of 0.2 (95% Confidence Interval [CI]: 0.1-0.5). Respondents under 25 years old were three times less likely to intend to receive the ARF vaccine compared to those 25 years old and above (AOR = 0.3; 95%, CI: 0.1-0.9). Conclusion: A considerable number of medical students were aware of the development of the ARF vaccine. This serves as a strong call to incorporate the teaching of ARF into the curriculum at all levels of medical education.