As a building block of lignins, guaiacol represents a large number of mono- and dimethoxy phenols found in bio-oil derived from soft- or hardwood, respectively. During lignin degradation by ozone-based processes, the intermediate product guaiacol is also oxidized by ozone. Traditionally, ozonation of organic wastewater is carried out in a bubble column. This study employed a rotating packed bed that used high rotating speed to enhance ozone mass transfer rate for guaiacol degradation. The effects of guaiacol initial concentration, ozone feed rate, rotating speed, and solution pH on the residual guaiacol concentration, residual chemical oxygen demand (COD) and total organic carbon (TOC) were experimentally measured. The experimental results show that the guaiacol, COD, and TOC degradation rates increase with increasing initial concentration, ozone feed rate, rotating speed, or solution pH. A kinetic model has been developed to predict the residual guaiacol concentration, residual COD and TOC satisfactorily.