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<i>Staphylococcus aureus</i> causes a wide range of infections, and it is one of the leading pathogens responsible for deaths associated with antimicrobial resistance, the rapid spread of which among <i>S. aureus</i> urges the discovery of new antibiotics. The evaluation of <em>in vivo</em> efficacy of novel drug candidates is usually performed using animal models. Recently, zebrafish (<i>Danio rerio</i>) embryos have become increasingly attractive in early drug discovery. Herein, we established a zebrafish embryo model of <i>S. aureus</i> infection for evaluation of <em>in vivo</em> efficacy of novel potential antimicrobials. A local infection was induced by microinjecting mCherry-expressing <i>S. aureus</i> Newman followed by treatment with reference antibiotics via microinjection into different injection sites as well as via waterborne exposure to study the impact of the administration route on efficacy. We successfully used the developed model to evaluate the <em>in vivo</em> activity of the natural product sorangicin A, for which common mouse models were not successful due to fast degradation in plasma. In conclusion, we present a novel screening platform for assessing <em>in vivo</em> activity at the antibiotic discovery stage. Furthermore, this work provides consideration for the choice of an appropriate administration route based on the physicochemical properties of tested drugs.