Monoamine Oxidase (MAO) play vital role in regulation of monoamine neurotransmitters such as serotonin, dopamine and nor-adrenaline. MAO inhibitors are used in the treatment of Parkinson’s disease, Alzheimer’s disease, depression etc. In present work we have carried out SAR analysis and developed many QSAR equations to understand the pharmacological activities of Xanthone derivatives as MAO inhibitors. The SAR and QSAR analysis provides interesting insights in understanding the hydrophobic, steric, electronic, and structural requirements for MAO inhibitory activity. Quantum mechanical studies support the SAR analysis. Combination of different types of 3-D descriptors like WHIM, GATEAWAY and so on provide useful QSAR models. The QSAR models were tested for their statistical significance by using Y-randomization, R2, R2 adj and R2 LOO methods. The significant model is with R2 > 91%. These QSAR studies help us in the design and prediction of novel Xanthone derivatives as MAO inhibitors.