Photocatalytic oxidation (PCO) is an innovative and promising technology for removing VOCs from indoor environment. However, partial oxidation of reactants generates by-products that could be more harmful to human health than parent compound. This paper presents the development of a by-products predictive model for the estimation of generated by-products based on the degradation reaction pathway of toluene in PCO. A one-dimensional mathematical model by considering the axially dispersed plug flow and Langmuir-Hinshelwood (L-H)-based reaction rate as well as linear source spherical emission (LSSE) model for the irradiation distribution on the media surface was developed for the prediction of the by-products concentration. Toluene was tested in a continuous flow PCO reactor with a commercial PCO filter under various operating conditions; concentrations (0.05–1 ppm), relative humidities (17–67%), flow rates (10–30 L/min), and irradiance (7–23.5 W/m2). Several by-products from various chemical groups, including aldehyde, ketone, alcohol and light acid, were identified by analytical instruments. Aldehydes were the major by-products of toluene in PCO, in which light aldehydes (acetaldehyde and formaldehyde) had a higher concentration among others. The result of curve fitting using the proposed model showed a high accuracy of the model (with R-squared greater than 0.98) for parameters estimation. Kinetic analysis of toluene indicated that the rate coefficients followed the order of benzaldehyde > propionaldehyde > acetaldehyde > formaldehyde. Benzaldehyde and propionaldehyde had a greater value of the kinetic coefficient in PCO because of higher adsorption tendency towards TiO2. Changes in operating conditions highly affected generation of by-products and the developed model could predict the concentration of toluene and the by-products with acceptable accuracy. The carbon balance analysis at residence time of 0.24 s showed 16.6% of toluene mineralized into carbon dioxide and it increased at longer residence time. The health risk index (HRI) analysis of toluene and its by-products was performed and found out that formaldehyde was the most influential pollutant on HRI due to very low recommended exposure limit and higher generated concentration.