A novel series of glabridin-chalcone hybrid molecules (GCHMs) were synthesized, evaluated for their antibacterial and resistance reversal activity against clinical isolates of methicillin resistant strain of Staphylococcus aureus (MRSA) alone and in combination with norfloxacin. Glabridin showed significant anti-staphylococcal activity against various MRSA clinical isolates with MICs 12.5 µg/ml. However, all its synthesized derivatives displayed moderate to weak activity (MICs ranging from 12.5- >100 µg/ml). Among all the synthesized hybrid molecules, compounds 6f, 6h, 8f and 8h along with glabridin were chosen for combination study with norfloxacin. Among all tested compounds, 8h exhibited marked synergism up to 16 folds reduction in MICs with norfloxacin (FICI range from 0.312-0.375). In systemically infected Swiss albino mice model, compound 8h significantly (p<0.01, p<0.05) lowered the systemic bacterial load in blood, liver, kidney, lung and spleen tissues. The present study reports the potential use of GCHMs in the development of economical anti-infective combinations for treatment of infection caused by clinical MRSA isolates.