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The progressive decrease in antibiotic efficacy is also compounded by a stagnating drug-discovery pipeline and underscores the urgent need for innovative and sustainable antimicrobial strategies. This review systematically delineates the core molecular mechanisms driving bacterial resistance, including enzymatic drug inactivation, target modification, reduced membrane permeability, and multidrug efflux pump overexpression. Furthermore, the potential of (flavonoids, alkaloids, and phenolics) as structurally diverse plant-derived compounds with multi-target activity is comprehensively assessed. The features of multi-target activity make them promising dual-function agents that may be capable of both direct antimicrobial action and resistance modulation. These natural products have distinct mechanisms from conventional antibiotics, low propensity for resistance, and versatile bioactivity as biofilm disruptors, enzyme inhibitors, and efflux pump blockers. Numerous phytochemicals exhibit potent synergistic effects with available antibiotics by effectively resensitizing resistant pathogens and extending the clinical utility of current antimicrobials. By integrating mechanistic understanding with translational potential, this review discusses phytochemicals as a sustainable resource for developing next-generation antimicrobial strategies as a complementary approach to revitalize therapeutic pipelines and combat multidrug-resistant infections.<\/jats:p>","DOI":"10.3390\/ijms27114804","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T16:17:58Z","timestamp":1779812278000},"page":"4804","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Medicinal Plants: A Promising Therapeutic Approach for Addressing Antimicrobial Resistance"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8640-1960","authenticated-orcid":false,"given":"Huanxin","family":"Zhou","sequence":"first","affiliation":[{"name":"College of Chemical Engineering and Technology, Taiyuan University of Science and Technology, No. 66 Waliu Road, Taiyuan 030024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinkang","family":"Du","sequence":"additional","affiliation":[{"name":"College of Chemical Engineering and Technology, Taiyuan University of Science and Technology, No. 66 Waliu Road, Taiyuan 030024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiyan","family":"Jia","sequence":"additional","affiliation":[{"name":"College of Chemical Engineering and Technology, Taiyuan University of Science and Technology, No. 66 Waliu Road, Taiyuan 030024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yine","family":"Li","sequence":"additional","affiliation":[{"name":"College of Chemical Engineering and Technology, Taiyuan University of Science and Technology, No. 66 Waliu Road, Taiyuan 030024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyun","family":"Zheng","sequence":"additional","affiliation":[{"name":"College of Chemical Engineering and Technology, Taiyuan University of Science and Technology, No. 66 Waliu Road, Taiyuan 030024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e0134121","DOI":"10.1128\/AAC.01341-21","article-title":"Antibiotic Use and Bacterial Infection among Inpatients in the First Wave of COVID-19: A Retrospective Cohort Study of 64,691 Patients","volume":"65","author":"Baghdadi","year":"2021","journal-title":"Antimicrob. 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