Background: The most recent variant of concern, omicron (B.1.1.529), has caused numerous cases worldwide including the Republic of Korea due to its fast transmission and reduced vaccine effectiveness. Methods: A mathematical model considering age-structure, vaccine, antiviral drugs, and influx of the omicron variant was developed. We estimated transmission rates among age groups using maximum likelihood estimation for the age-structured model. The impact of non-pharmaceutical interventions (NPIs; in community and border), quantified by a parameter μ in the force of infection, and vaccination were examined through a multi-faceted analysis. A theory-based endemic equilibrium study was performed to find the manageable number of cases according to omicron- and healthcare-related factors. Results: By fitting the model to the available data, the estimated values of μ ranged from 0.31 to 0.73, representing the intensity of NPIs such as social distancing level. If μ < 0.55 and 300,000 booster shots were administered daily from February 3, 2022, the number of severe cases was forecasted to exceed the severe bed capacity. Moreover, the number of daily cases is reduced as the timing of screening measures is delayed. If screening measure was intensified as early as November 24, 2021 and the number of overseas entrant cases was contained to 1 case per 10 days, simulations showed that the daily incidence by February 3, 2022 could have been reduced by 87%. Furthermore, we found that the incidence number in mid-December 2021 exceeded the theory-driven manageable number of daily cases. Conclusion NPIs, vaccination, and antiviral drugs influence the spread of omicron and number of severe cases in the Republic of Korea. Intensive and early screening measures during the emergence of a new variant is key in controlling the epidemic size. Using the endemic equilibrium of the model, a formula for the manageable daily cases depending on the severity rate and average length of hospital stay was derived so that the number of severe cases does not surpass the severe bed capacity.