The concept of “synergy” and its applications has rapidly increased in the food industry as a practical strategy to preserve and improve health-promoting effects of the functional ingredients. In this study, hydrophilic epigallocatechin-3-gallate (EGCG) and lipophilic lycopene (LYC) were loaded separately (EGCG loaded PDE (PE), and LYC loaded PDE (PL), and also co-delivered (PEL) within a pickering double emulsion (PDE) system to induce synergistic hypolipidemic effect. Their effects on the serum lipid profile, weight of tissue fats, liver lipid droplet accumulation, and liver steatosis in a high-fat diet rat model were investigated. Moreover, different pathways (HMG-CoR, LDL-R, PPARγ and AMPK) involved in triggering hypolipidemic effects were verified at both mRNA and protein levels. The study's findings showed that inclusion of EGCG improved while LYC negatively affected the physical stability of PDE. The contents of total cholesterol and triacylglyceroles in serum and liver as well as the weight of tissue fats were substantially reduced in all groups (PE/PL/PEL). The alteration in absorption site of EGCG and enhanced bioaccessibility of LYC when delivered by PDE strengthened the hypolipidemic properties of PE and PL, mainly through triggering the pathways of HMG-CoR, LDL-R and PPARγ. Furthermore, the synergistic hypolipidemic effect of PEL was achieved mainly through the activation of the AMPK pathway.