Food safety studies have received much empirical investigation; however, limited studies regarding food safety and the microbiological quality of meals in boarding senior high schools exist. This study examined the food safety knowledge, the microbiological quality of school meals, as well as the barriers to food safety practices among food handlers in boarding senior high schools (SHS) in the Volta Region of Ghana. A cross-sectional research design was adopted for the study, using questionnaires to collect data from 97 food handlers in five boarding senior high schools in Volta Region, Ghana. A total of sixty samples of four cooked foods were collected and subjected to laboratory analysis. Descriptive statistics and Chi-square test were used to analyze the data. Results of the study revealed that respondents had good food safety knowledge. The laboratory results revealed the presence of rod and cocci shaped bacteria, where some of these isolates were identified as Escherichia coli, Staphylococcus aureus, Pseudomonas spp., and Bacillus cereus which are possible pathogens. The barriers to food safety practices revealed inadequate provision of equipment and irregular water supply. Findings of this study have implication for stakeholders involved in the management of SHS. Administrators of SHSs must design and implement food hygiene training and sanitation programmes for food handlers in schools. Also, more stringent supervision during food preparation processes is recommended.