In the present work,heat–CaO2 advanced thermal hydrolysis pretreatment was applied for enhancing fermentative short-chain fatty acids (SCFAs) production from waste activated sludge (WAS). Various pretreatment conditions including heating temperatures, CaO2 doses, and times were optimized. Simulation and experimental results showed that the optimal pretreatment conditions were a temperature of 67.4 °C, CaO2 of 0.12 g/g VSS, and time of 19 h, under which the maximum SCFAs yield reached to 336.5 mg COD/g VSS after 5 days of fermentation, with the percentage of acetic acid accounted for 70.1%. Mechanism investigations exhibited that CaO2 and heat pretreatment caused positive synergy on sludge solubilization and SCFAs production. Compared with the control, heat pretreatment, and CaO2 addition alone, the heat–CaO2 pretreatment not only facilitated the organic released from WAS but also increased the proportion of biodegradable organic matters, which thereby providing more organics for subsequent SCFA production. It was found that the heat–CaO2 pretreatment improved the activities of both hydrolytic and acid-forming enzymes while it inhibited the coenzymes of methanogens during the fermentation process. In addition, heat–CaO2 pretreatment and subsequent fermentation worked well in removal of refractory organic pollutants and pathogens contained in WAS. Further analysis indicated that the heat–CaO2 pretreatment can be used as an effective method for both valuable carbon source recovery and refractory pollutant removal in the WAS treatment process.