Staphylococcus aureus is a common multidrug-resistant organism in hospital-acquired infections, and the NorA efflux pump mechanism facilitates resistance to quinone compounds. In India, Wrightia tinctoria R. Br. leaves have traditionally been used to treat skin diseases and have been explored for antibacterial and efflux pump inhibition (EPI) compounds. In this study, indirubin isolated from the chloroform extract of W. tinctoria R. Br. leaves was tested for its antibacterial activity against clinically important Gram-positive and Gram-negative bacteria and the minimum inhibitory concentration (MIC) was determined using broth microdilution. The EPI properties of indirubin were investigated using Staphylococcus aureus SA1199B, and its synergistic effects were tested with ciprofloxacin. Indirubin showed antibacterial activity against both the type strain and drug-resistant S. aureus; the MIC was determined to be 12.5 mg/l for S. aureus and 25 mg/l for Staphylococcus epidermidis. However, it synergistically (fractional inhibitory concentration index = 0.45) potentiated the activity of ciprofloxacin, probably by inhibiting the NorA efflux pump. Indirubin exhibited EPI activity nearly comparable to that of reserpine by 4-fold reduction in ciprofloxacin MIC. Our results suggest that the natural compound indirubin could be used in future therapeutic applications as a potential EPI.