Amphiphilic polymers have now been designed to achieve an icephobic performance and have been used for ice adhesion prevention. They may function by forming a strongly bonded but nonfreezable water shell which serves as a self-lubricating interfacial layer that weakens the adhesion strength between ice and the surface. Here, an analogous concept is built to prevent the formation of clathrate hydrate compounds during oil and natural gas production, in which amphiphilic water-soluble polymers act as efficient kinetic hydrate inhibitors (KHIs). A novel group of copolymers with N-vinylcaprolactam and N-acryloylpyrrolidine structural units are investigated in this study. The relationships among the amphiphilicity, lower critical solution temperature, nonfreezable bound water, and kinetic hydrate inhibition time are analyzed in terms of the copolymer compositions. Low-field NMR relaxometry revealed the crucial interfacial water in tightly bound dynamic states which led to crystal growth rates changing with the copolymer compositions, in accord with the rotational rheometric analysis results. The nonfreezable bound water layer confirmed by a calorimetry analysis also changes with the polymer amphiphilicity. Therefore, in the interface between the KHI polymers and hydrate, water surrounding the polymers plays a critical role by helping to delay the nucleation and growth of embryonic ice/hydrates. Appropriate amphiphilicity of the copolymers can achieve the optimal interfacial properties for slowing down hydrate crystal growth.