This study aims to investigate the toughening effects of rubber and thermoplastic particles on epoxy resin (EP), and to understand the mechanism underlying their synergistic effect. For this purpose, three EP systems were prepared using diglycidyl ether of bisphenol-A (DGEBA) epoxy resin (E-54) and 4,4-Diamino diphenyl methane (Ag-80) as matrix resin, 4,4-diaminodiphenyl sulfone (DDS) as a curing agent, and phenolphthalein poly (aryl ether ketone) particles (PEK-C) and carboxyl-terminated butyl liquid rubber (CTBN) as toughening agents. These systems are classified as an EP/PEK-C toughening system, EP/CTBN toughening system, and EP/PEK-C/CTBN synergistic toughening system. The curing behavior, thermal properties, mechanical properties, and phase structure of the synergistic-toughened EP systems were comprehensively investigated. The results showed that PEK-C did not react with EP, while CTBN reacted with EP to form a flexible block polymer. The impact toughness of EP toughened by PEK-C/CTBN was improved obviously without significantly increasing viscosity or decreasing thermal stability, flexural strength, and modulus, and the synergistic toughening effect was significantly higher than that of the single toughening system. The notable improvement in toughness is believed to be due to the synergistic energy dissipation effect of PEK-C/CTBN.