The specific air jet of a diffuser is formed by the complex internal structure, which affects the outlet airflow distribution of the diffuser directly and the indoor environment distribution indirectly. If the diffusers are developed based on their actual geometry structure and their boundary conditions are set as their inlet flowrate, the simulated indoor temperature distribution will be more accurate. However, it is noted that many problems may arise, such as model complexity, many grid cells, and slow convergence of calculations. Therefore, this paper focuses on a simplified method for four-way square diffusers in a computational fluid dynamics (CFD) simulation of indoor non-uniform temperature distribution. Firstly, the airflow distribution is simulated on the outlet air supply cross-section of the diffuser. Then, according to the outflow characteristics of the diffuser, the diffuser model is simplified and simulated in an experimental room. Finally, the temperature distribution at the 1.2 m height plane is obtained from CFD simulation and compared with the experimental results. The results show that the 68-point air supply opening model can well simulate the effects of the outlet airflow distribution of the diffuser, and the simulated indoor temperature distribution meets the experiment results well. The deviations for three scenarios are between −7.4~1.7% and the average deviation is −3.0%, while the root mean square error of temperature for three scenarios is 0.7 °C, 0.7 °C, and 1.0 °C, respectively. The results also demonstrate the mutual influence of the airflow from different diffusers and the indoor non-uniform temperature distribution under the action of multiple diffusers. The proposed method can contribute to balancing the model complexity and the accuracy in CFD simulation, especially for multiple diffusers in the room.