Introduction: Hospital-acquired infections (HAIs) also known as a nosocomial infection is associated with increased morbidity and mortality among hospitalized clients and predisposes health care workers (HCWs) to an increased risk of infections. Therefore, an effective Infection Prevention and Control (IPC) programme is fundamental to quality health care. This study looked at the knowledge of and compliance with infection prevention and control among Nurses at the Northern Regional Hospital Tamale, Ghana. The goal of this study was to assess the knowledge level and compliance with infection prevention and control practices among Nurses in the Northern Regional hospital Tamale, Ghana. Methodology: The study adopted a facility-based descriptive cross-sectional study. Data were collected from 268 staff nurses at Central Hospital, Tamale. A mixed-method was employed and using Self- administered questionnaire and key informant interview guide. Data were collected and entered into IBM SPSS V. 21 for analysis. Results: At the Northern Regional Hospital majority (60.5%) of the respondents had high IPC knowledge, 25.8% had moderate IPC knowledge level and only 13.8% had low IPC knowledge level. The findings on IPC compliance revealed that majority (77.6%) of the respondents had a low IPC compliance level, 19.8% had a moderate IPC compliance level and only 2.6% had a high IPC compliance level. Conclusion: Although the study revealed that most of the respondents had good knowledge of the IPC. However, compliance with IPC guidelines was still very low in the hospital. It was observed from the study that, the hospital has limited access to IPC training manuals couple with inadequate IPC materials such as Hand hygiene materials and Personnel protective equipment (PPEs). The Ghana Health Service in collaboration with the Ministry of Health should intensify monitoring and supervision at all levels of service delivery points to ensure health care providers compiles with IPC standard protocols. The Ghana Health Service, Ministry of Health and Development Partners should ensure IPC materials are in constant supply and made available to all health care service points. The Hospital should regularly conduct refresher training on current IPC standards and ensure compliance through effective monitoring. Health staff should make conscious efforts to protect themselves and clients against infections by ensuring that IPC standards and protocols are strictly followed in the discharge of their duties.