Background <p>Cervical cancer (CC) causes significant morbidity and mortality in low-and middle-income settings, ranking second commonest female cancer in Ghana, affecting 26.4/100,000 with mortality rate 22.9/100,000 women.</p> <p>Previous studies focused on adults, females and involved smaller sample sizes. This study assessed CC knowledge among secondary school students in Ghana to generate evidence for implementing school-based educational interventions.</p> Methods <p>It was a multi-site, cross-sectional study across 14 secondary schools in Greater Accra (GAR) and Central regions(C/R) of Ghana. Self-administered pre-tested questionnaires focused on students’ knowledge on causes, risk factors, symptoms, and prevention of CC. Four main domains were covered: general knowledge; cervical cancer features; risk factors; and screening and prevention. Domain scores were categorised into adequate knowledge (&gt;50%) and inadequate knowledge (&lt; 50%). Chi-square was used to test association between knowledge in various domains with participants’ gender, school type, and region. P-value below 0.05 was considered statistically significant.</p> Results <p>A total of 9,767 students from 14 schools, 25.6% (n=2,280) males and 74.4% (n=6,630) females with mean age 16.9+1.2years participated. Overall, 58.4% of students had adequate general knowledge about CC; 61.1% demonstrated adequate knowledge of risk factors; 21.5% adequate knowledge of features, and 51.8% also had adequate knowledge of screening and prevention. Across all domains tested, 60.6%% of students had inadequate knowledge. More female students(60.9%) had adequate general knowledge than males(50.1%) (p&lt; 0.001).</p> Conclusion <p>Significant knowledge gaps exist on risk factors, features, screening and prevention of cervical cancer among senior high school students in Ghana, necessitating targeted educational interventions based on identified gaps.</p>