Clathrate hydrate particle agglomeration is often considered to be one of the key limiting factors in plug formation. The hydrate particle–water interaction can play a critical role in describing hydrate agglomeration, yet is severely underexplored. Therefore, this work investigates the interactions between water droplets and cyclopentane hydrate particles using a micromechanical force (MMF) apparatus. Specifically, the effect of contact time, temperature/subcooling, contact area, and the addition of Sorbitane monooleate (Span 80) surfactant on the water droplet–hydrate particle interaction behavior are studied. The measurements indicate that hydrate formation during the measurement would increase the water–hydrate interaction force significantly. The results also indicate that the contact time, subcooling and concentration of cyclopentane, which determine the hydrate formation rate and hydrate amount, will affect the hydrate–water interaction force. In addition, the interaction forces also increase with the water–hydrate contact area. The addition of Span 80 surfactant induces a change in the hydrate morphology and renders the interfaces stable versus unstable (leading to coalescence), and the contact force can affect the hydrate–water interaction behavior significantly. Compared with the hydrate–hydrate cohesion force (measured in cyclopentane), the hydrate–water adhesion force is an order of magnitude larger. These new measurements can help to provide new and critical insights into the hydrate agglomeration process and potential strategies to control this process.