Mechanical and natural ventilations are effective measures to remove indoor airborne contaminants, thereby creating improved indoor air quality (IAQ). Among various simulation techniques, Markov chain model is a relatively new and efficient method in predicting indoor airborne pollutants. The existing Markov chain model (for indoor airborne pollutants) is basically assumed as first-order, which however is difficult to deal with airborne particles with non-negligible inertial. In this study, a novel weight-factor-based high-order (second-order and third-order) Markov chain model is developed to simulate particle dispersion and deposition indoors under fixed and dynamic ventilation modes. Flow fields under various ventilation modes are solved by computational fluid dynamics (CFD) tools in advance, and then the basic first-order Markov chain model is implemented and validated by both simulation results and experimental data from literature. Furthermore, different groups of weight factors are tested to estimate appropriate weight factors for both second-order and third-order Markov chain models. Finally, the calculation process is properly designed and controlled, so that the proposed high-order (second-order) Markov chain model can be used to perform particle-phase simulation under consecutively changed ventilation modes. Results indicate that the proposed second-order model does well in predicting particle dispersion and deposition under fixed ventilation mode as well as consecutively changed ventilation modes. Compared with traditional first-order Markov chain model, the proposed high-order model performs with more reasonable accuracy but without significant computing cost increment. The most suitable weight factors of the simulation case in this study are found to be (λ1 = 0.7, λ2 = 0.3, λ3 = 0) for second-order Markov chain model, and (λ1 = 0.8, λ2 = 0.1, λ3 = 0.1) for third-order Markov chain model in terms of reducing errors in particle deposition and escape prediction. With the improvements of the efficiency of state transfer matrix construction and flow field data acquisition/processing, the proposed high-order Markov chain model is expected to provide an alternative choice for fast prediction of indoor airborne particulate (as well as gaseous) pollutants under transient flows.