In this study, a systematic analysis of the effect of three biomass pyrolysis oxygenates, viz., acetic acid, cyclopentanone and furfural, on the hydrodeoxygenation (HDO) of guaiacol is performed. Bifunctional Pt/HY catalysts with different Si/Al ratios were screened for the HDO of guaiacol. Guaiacol conversion and the cyclohexane yield increased with the concentration of acid sites in the zeolites. The presence of acetic acid and cyclopentanone did not affect the guaiacol conversion and the product selectivity, while guaiacol conversion decreased significantly in the presence of furfural. The effects of temperature, reaction time, and the guaiacol-furfural molar ratio on the HDO of guaiacol were studied. The time evolution of products showed that the furan ring opening influences the conversion of guaiacol. Quantum chemical density functional theory calculations using individual and binary model compounds revealed the decrease in adsorption energy of guaiacol over Pt (1 1 1) in the presence of furfural.