Background Knowledge of and compliance to infection prevention and control (IPC) guidelines are crucial to curbing hospital acquired infections (HAIs). Globally, about 7–10% of patients suffer HAIs. However, there is limited evidence on nurses’ knowledge and adherence to IPC guidelines. Therefore, this study assessed the knowledge and determinants of IPC compliance among nurses in Yendi Municipality, Northern Ghana. Methods We conducted a quantitative cross-sectional study among 209 nurses of the Yendi Municipal hospital, using an adapted questionnaire. We collected and analysed data using SPSS version 26. Socio-demographics, knowledge level and compliance to IPC guidelines were assessed using descriptive statistics. The minimum scores for knowledge and compliance were 0 each with maximum scores being 10 and 8 respectively. Using binary multivariate logistic regression, the determinants of IPC compliance were analysed and odds ratios reported at 95% confidence intervals. Results The nurses had high mean and standard deviation scores for knowledge (7.26 ± 1.4) and compliance to IPC guidelines (5.41 ± 1.5). Females (aOR: 0.33; 95%CI: 0.17–0.64; p = 0.001) were significantly less likely to comply to IPC guidelines. Nurses working in Maternity/Labour wards (aOR: 8.31; 95%CI: 2.46–28.15; p = 0.001) and Outpatient Department (OPD)/Psychiatry (aOR: 5.00; 95%CI: 1.42–17.62; p = 0.012) were associated with higher odds of complying to IPC guidelines. Availability of IPC guidelines (aOR: 3.48; 95%CI: 1.13–10.72; p = 0.030) in a working department influenced compliance to IPC measures. Conclusion The study revealed high knowledge and high compliance regarding IPC among nurses in the Yendi Municipal Hospital. A person’s working department and the availability of IPC guidelines were key determinants for high compliance to IPC measures. However, knowledge of IPC did not influence compliance to IPC guidelines. The Municipal and Regional Health directorates, should therefore ensure adequate logistic flow, provision of IPC guidelines and proper supervision to ensure maximum compliance with IPC guidelines, particularly among paediatric, medical and surgical wards nurses as well as degree holding nurses.