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Background: The emergence of COVID-19 posed a threat to millions of lives worldwide. The pandemic impacts extended to affect people's psychological well-being, resulting in significant behavioural change. This study was designed to assess the knowledge regarding COVID-19 precautions among the College of Applied Medical Science students at Jazan University and to evaluate the general, psychosocial, and behavioral changes due to COVID-19. Methods: This is an observational study targeting 630 undergraduate students randomly selected during January 2020, using stratified random sampling. Data were collected using an online questionnaire. Linear regression models were used to evaluate the predictors of three outcome measures: knowledge, attitudes, and practice scores. Results: Knowledge of COVID-19 revealed that the students with correct answers ranged from 48.9 to 95%. Furthermore, significant gender differences are found regarding shortness of breath, fatigue, persistent chest discomfort, headache, and malaise (p < 0.05). Knowledge scores differed significantly across gender and academic level (p < 0.05) and so does attitude scores (p < 0.05). No significant difference was observed between practice scores according to socio-demographic background (p > 0.05). The linear regression model showed that females had significantly higher knowledge, attitudes, and practice scores (p < 0.05) as well as those within the 21– 23 age group and above (p < 0.05). Students residing in urban and semi-urban places had significantly higher scores for knowledge, attitudes, and practice (p < 0.05). Conclusion: The results demonstrated moderate knowledge about COVID-19 among study participants, with significant differences between the responses of males and females and among the urban and rural populations. Outcomes suggest the need for interventions to bridge students' knowledge about COVID-19 and practice gaps. Students were concerned about basic life amenities and the inability to provide for their dear ones regarding behavioral changes. [ABSTRACT FROM AUTHOR]