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FDA-drug repurposing is an important therapeutic tactic to fight MDR bacteria. Here, we inspected the antibacterial activity of ambroxol against clinical MDR <jats:italic>S. aureus<\/jats:italic> isolates. Using the broth microdilution method, ambroxol revealed minimum inhibitory concentrations (MICs) of 0.75 to 1.5\u00a0mg\/mL. Also, it revealed antibiofilm action on 42.17% of the isolates by crystal violet assay. A scanning electron microscope was employed to study the antibiofilm action of ambroxol. It revealed that the association between the cells was interrupted by ambroxol, and the biofilm construction was devastated. Moreover, qRT-PCR was utilized to elucidate the consequence of ambroxol on the gene expression of efflux and biofilm. Remarkably, ambroxol has downregulated the expression of <jats:italic>cna<\/jats:italic>, <jats:italic>fnb<\/jats:italic> A, <jats:italic>ica<\/jats:italic>, <jats:italic>nor<\/jats:italic> A, <jats:italic>nor<\/jats:italic> B genes. Ambroxol\u2019s in vivo antibacterial action was investigated using <jats:italic>S. aureus<\/jats:italic> infected burn infection. Interestingly, ambroxol has improved the histological features of the skin tissues, significantly diminished the bacterial burden, and increased the wound healing percentage. Also, it revealed a significant reduction in the immunohistochemical staining of tumor necrosis factor-alpha. Finally, the in silico investigations were performed to elucidate the potential of ambroxol on five possible targets of <jats:italic>S. aureus.<\/jats:italic> Ambroxol showed good affinities on the five investigated targets in <jats:italic>S. aureus<\/jats:italic>, with CrtM being the highest, proposing its probable role in the mechanisms for ambroxol\u2019s action on <jats:italic>S. aureus.<\/jats:italic><\/jats:p>","DOI":"10.1186\/s12866-024-03666-x","type":"journal-article","created":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T07:35:07Z","timestamp":1732865707000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Unveiling the antibacterial action of ambroxol against Staphylococcus aureus bacteria: in vitro, in vivo, and in silico investigation"],"prefix":"10.1186","volume":"24","author":[{"given":"Ahmed A.","family":"Abdelaziz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal M.","family":"Abo-Kamar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa E.","family":"Ashour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moataz A.","family":"Shaldam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Engy","family":"Elekhnawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,29]]},"reference":[{"key":"3666_CR1","doi-asserted-by":"crossref","unstructured":"Bharadwaj A, Rastogi A, Pandey S, Gupta S, Sohal JS. 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