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Porcine epidemic diarrhea virus (PEDV) causes severe enteric disease in swine and continues to impose substantial economic losses on the global pig industry. Understanding the host determinants that govern PEDV entry is therefore critical for elucidating the mechanisms of infection. Here, we show that efficient PEDV entry is closely associated with intact and functional intracellular cholesterol transport in host cells. We identified the cholesterol transporter Niemann-Pick C1 (NPC1) as a critical host factor required for PEDV entry and demonstrated that NPC1 facilitates viral internalization through direct interaction with the S2 subunit of the PEDV spike protein. In addition, coordinated functions of the NPC1/NPC2 cholesterol transport system are involved in this process. By revealing the functional dependence of PEDV entry on host cholesterol trafficking, this study highlights this pathway as a potential target for therapeutic intervention.