Background: Hand hygiene is recognized as the leading measure to prevent cross-transmission of COVID-19. The compliance of nurses with handwashing guidelines is vital in preventing COVID-19 disease transmission among patients. Globally, few studies have explored this subject, especially on the nursing students’ perceptions and barriers of standard hand hygiene precautionary measures amidst the COVID-19 pandemic.  Purpose: The study aimed to assess the perceptions and barriers associated with standard hand hygiene practice during the COVID-19 era among first degree nursing students undertaking their clinical rotation at the Tamale Teaching Hospital of Ghana. This study was conducted in April 2021.    Materials and methods: The study employed a descriptive cross-sectional design with a quantitative approach. The study population consisted of first degree student nurses of the University for Development Studies who were on clinical rotation at the Tamale Teaching Hospital in the Northern Region of Ghana. The exclusion criteria were nursing students from other tertiary institutions who were having their vacation practicum at the hospital. A simple random sampling technique was used to select the study participants from the wards of the hospital. A standard statistical formula was used to arrive at a sample size of 120. Data was collected by using a paper-based self-designed structured questionnaire in English language that has closed- and open-ended questions. Descriptive statistics involving frequencies and percentages were used in representing data. By using a chi-square test, a p-value <0.05 was considered statistically significant when the association between independent and dependent variables was cross-tabulated. The statistical software that was used for analyzing the data was SPSS version 23.      Results: The study had a total of 120 participants with a mean age of 26.48 and a standard deviation of 3.49. On the distribution of perception about hand hygiene, findings indicated that 105 (87.5%) had good perception. Religion and sex respectively were significantly associated with hand hygiene perceptions (χ2= 13.118, p=0.011; χ2=12.49, p=0.014). Conclusion: Though few of the student nurses had a satisfactory perception regarding hand hygiene, it is a cause to worry about since there exist other barriers influencing standard hand hygiene practices at the Tamale Teaching Hospital. Recommendation: There is the need for the quality assurance unit of the hospital to ensure strict compliance to COVID-19 protocols by all categories of health professionals by seeing to it that standard hand hygiene practices are adhered to, irrespective of religious background.