Air change times and differential pressure (DP) gradient are important indicators for measuring the cleanliness of a cleanroom. In the traditional dust-free room, the control requirements of supply air volume (Gs) and DP balance are usually achieved by adjusting fan frequency and angle of the constant air volume valve or variable air volume valve, which wastes remarkable amounts of time, money and cannot achieve accurate regulation. Therefore, based on the analysis of cleanroom model, a Gs balance adjusting strategy (SAVS) and DP adjustment algorithm (DPGA) were proposed. After the influence of a multi-room Gs adjustment sequence was analyzed, the SAVS was found to achieve Gs balance in a multi-room area. Based on constant Gs, a theoretical analysis of differential pressure air volume, and adjustments of the distribution of return air volume and exhaust air volume, the DPGA realized the stability of DP gradient in the multi-room area. In the experimental verification of the model, the relevant errors of total Gs, total fresh air volume, and total exhaust air volume of system were within [–143, 265] m3/h. Compared with the room Gs calculated by the algorithm, the Gs error was maintained within [–1.8%, 5.3%]. Compared with the room DP calculated by the algorithm, the DP error was maintained within [–1.9, 1.3] Pa. Using the SAVS and DPGA, the energy consumption of the cleanroom operation was reduced by 18.58%. The system scheme is provided for cleanroom cleanliness and pressure difference control, and the energy consumption of the system is reduced.