The rising threat of antimicrobial resistance necessitates the search for novel bioactive molecules from natural sources. This study investigated the phytochemical composition, antibacterial potency, and molecular docking interactions of Citrus aurantium peel ethanol extract against Escherichia coli outer membrane and topoisomerase proteins and Staphylococcus aureus toxins as drug target proteins. Qualitative and quantitative phytochemical compositions were examined using standard analytical methods, chemical compounds were evaluated and qualified using Gas Chromatography–Mass Spectrometry (GC-MS), antibacterial effects were investigated in silico and validated in vitro. Qualitative and quantitative analyses revealed high concentrations of flavonoids (4.54 ± 0.11 %), alkaloids (1.6 ± 0.03%), terpenoids (1.35 ± 0.01%), tannins (1.02 ± 0.05%), phenols (0.97 ± 0.07%), and saponins (0.80 ± 0.01%). GC–MS profiling identified several dominant compounds, including β-D-glucopyranose, neo-inositol, 8-(2,3-dihydroxy-3-methylbutyl)-7-methoxy-2H-chromen-2-one, and D-allose. In silico docking studies against bacterial druggable proteins (PDB IDs: 4C56 and 3MFG, which are S. aureus toxins; 1BXW, and 3FV5, which are E. coli outer membrane and topoisomerase proteins) revealed strong binding affinities (–6.477 to –8.774 kcal/mol), comparable to standard antibiotics. ADMET predictions confirmed favorable pharmacokinetic and safety profiles, with most lead compounds displaying high intestinal absorption, low hepatotoxicity, and compliance with Lipinski’s rule of five. The extract exhibited stronger antibacterial activity, producing inhibition zones of 25.11±0.017 and 23.04±0.25 mm against clinical isolate of S. aureus and E. coli, respectively, at a concentration of 10 mg/ml, comparable to ciprofloxacin (30.35 ± 0.26 mm). These findings highlight C. aurantium peel phytoconstituents as promising scaffolds for antibacterial drug development and justify further in vivo validation for combating multidrug-resistant pathogens.