Multidrug-resistance in Staphylococcus aureus is a global health concern. Alternative strategies to battle antibiotic resistance with novel antimicrobials is of prime importance in the current times. Plant bioactive compounds in combination with antibiotics have proven effective for modulating the antibiotic resistance of various drug-resistant bacteria. Artemisia vulgaris L. is a common herbaceous plant used in traditional medicine. This study evaluated the synergistic activity of methanol extract of the leaves of Artemisia vulgaris L. with selected antibiotics directed against clinical isolates of multidrug-resistant Staphylococcus aureus. The plant extract concentration of 500 mg/ml exhibited the largest zone of inhibition of 23.33 ± 0.57 mm against the isolate SA 05. The minimum inhibitory concentration of the plant extract determined was 3.90 mg/ml and the minimum bactericidal concentration was 7.81 mg/ml against isolates SA 08 and SA 10, respectively. The MBC/MIC value of ≤4 exhibited a bactericidal effect of the extract against most of the tested clinical isolates. The methanol extract of A. vulgaris showed synergistic activity with oxacillin and clindamycin against all the clinical isolates of S. aureus. Synergistic activity was also exhibited with penicillin, gentamicin, and ciprofloxacin against most of the clinical isolates. Thirty phytocompounds were detected in the extract of A. vulgaris by Gas chromatography-Mass spectrometry analysis. Results have revealed potential antibiotic resistance modulatory property of A. vulgaris against multidrug-resistant S. aureus through synergistic action with antibiotics.