In this study, a novel oxy-fuel cascade thermo-photovoltaic (TPV) system concept was proposed and researched. Oxy-fuel combustion was used to reduce NOx emissions and the proposed cascade design and an increase in oxygen ratio were used to enhance the TPV system output. A physical model was established to conduct thermodynamic calculations to determine the influence of the cascade design and oxygen ratio on the system performance under oxy-fuel conditions. Moreover, the optimal area distribution of the cascade TPV and its influencing factors were determined and a preliminary assessment of the emission reduction potential was conducted. The results showed that the cascade design improved the system efficiency and a comprehensive comparison indicated the superiority of the two-stage TPV. An increase in the oxygen ratio under oxy-fuel conditions increased the system efficiency and resulted in considerable NOx emission reduction. Moreover, the multi-stage TPV system has an optimal area distribution, and an increase in the oxygen ratio increased the optimal area of the first stage. This study provides a reference for the design of high-efficiency TPV energy conversion systems.