Background: COVID-19 Omicron variant is spreading in alarming way universally. Thus, assessing knowledge, anxiety and preventive behaviors of every individual is essential in handling the outbreak effectively. Aim of the study: To assess knowledge, level of anxiety and protective behaviors regarding Omicron among secondary school students. Design: A descriptive cross sectional study design was utilized. Setting: This study was conducted in five secondary schools allocated in five educational directorates in El-Beheira governorate, Egypt. Subjects: Convenient sample of five hundred students were selected from the previous settings. Tools for data collection: Two tools were used. Tool I: Structured self-administered questionnaire including two parts. Tool II: COVID-19 Induced Anxiety and Protective Behaviors during COVID-19 Outbreak Scale. Results: More than half of the students had poor knowledge and low protective behaviors towards omicron (52.6% and 52.4% respectively). Additionally, more than half of the studied sample reported high level of anxiety regarding omicron. Moreover, age from 14 to less than 16 years, being female, living in rural area, their parents not working, having no previous infection of COVID-19, having a family member infected with COVID-19, poor knowledge concerning omicron and displaying high protective behaviors toward COVID-19 are associated with anxiety. Conclusion: It can be concluded that, the highest percentage of the students reported poor knowledge, high anxiety level and displayed low protective behaviors toward Omicron. Recommendations: Conducting digital based and traditional educational interventions to raise the student's awareness concerning omicron and reduce their anxiety.