In recent years, growing public concern over indoor air quality (IAQ) and building energy efficiency has placed greater demands on more cost-effective ventilation strategies. Currently, mechanical ventilation (MV) is widely applied in public buildings. However, the continued practice of minimum ventilation rate (VR)-based MV accounts for over 40% of the building’s total energy consumption, posing a challenge to carbon emission reduction. This study proposes an energy-efficient new ventilation mode integrating MV with portable air cleaners (PACs). The investigation methodology is as follows: First, targeting typical indoor air pollutants (IAPs, i.e., PM0.3–10, O3, TVOC, CO2, and UFPs), we established the dynamic models under three ventilation modes of MV alone, PAC alone, and MV combined with PAC. Second, we conducted a twin-chamber study to measure IAP concentrations under three ventilation modes. Subsequently, the cleaning efficiencies for different IAPs were obtained and compared using the Levenberg-Marquardt algorithm, while the factors impacting the efficiency were discussed. Finally, the accuracy of the prediction model for the MV-PAC combined system was validated, and the energy consumption advantage was analyzed. Our study demonstrates that integrating MV with PACs can reduce IAP concentrations with lower energy consumption.