The Coronavirus Disease, 2019 (COVID-19) disrupted healthcare delivery. Health workers, particularly nurses are key members of the interdisciplinary healthcare team. They are faced with many challenges due to the pandemic. In addition to providing basic healthcare services, nurses are required to adhere to the COVID-19 recommended safety protocols. This study explored experiences of nurses on the implementation of COVID-19 preventive protocols in Tamale Metropolis, Ghana. A qualitative study was conducted among seventeen (17) nurses, comprising five (5) staff with COVID-19 infection, and twelve (12) ward managers or in-charges who did not have COVID-19 infection, using explorative design and an interview guide. The participants were purposively selected. The ward managers/in-charges and infected staff were interviewed face-to-face and by mobile phone respectively. Content analysis was conducted on the data and the results presented as themes and sub-themes. After the analysis, five (5) main themes and fourteen (14) sub-themes were identified on experiences of nurses regarding COVID-19 preventive protocols implementation. These included understanding COVID-19 transmission/spread (patients-to-staff, staff-to-staff and through fomites), communicating the preventive protocols (social media, ward meetings and administrative memoranda), and attitude of nurses on the protocol’s implementation (growing apathy, discomfort in applying personal protective equipment (PPEs) and outright defiance). Nurses also experienced some challenges and inadequate support (progressive decline in supply of PPEs, infrequent supply of water and limited infrastructure), in addition to dealing with issues of protocols implementation in healthcare setting (inapplicability of social distancing in hospital setting and improvising PPEs). In conclusion, the nurses had varied experiences on COVID-19 preventive protocols implementation. The themes explored were mode of COVID-19 transmission, communication approaches, negative attitudes, inadequate logistics and inability to implement social distance. Overall, these affected the effective implementation of the protocols. Thus, health facilities should be provided with adequate logistics/supplies and trainings to enable nurses implement COVID-19 preventive protocols effectively.