Liquid droplets offer a great number of opportunities in biochemical and physical research studies in which droplet-based microlasers have come into play over the past decade. While the recent emergence of droplet lasers has demonstrated their powerful capabilities in amplifying subtle molecular changes inside the cavity, the optical interactions between droplet resonators and an interface remain unclear. We revealed the underlying mechanism of droplet lasers when interacting with a droplet–solid interface and explored its correlation with intermolecular forces. A vertically oriented oscillation mode—arc-like mode—was discovered, where the number of lasing modes and their Q-factors increase with the strength of interfacial hydrophobicity. Both experimental and theoretical results demonstrated that hydrophobicity characterized by contact angle and interfacial tension plays a significant role in the geometry of droplet cavity and laser mode characteristics. Finally, we demonstrated how tiny forces induced by proteins and peptides could strongly modulate the lasing output in droplet resonators. Our findings illustrate the potential of exploiting optical resonators to amplify intermolecular force changes, providing comprehensive insights into lasing actions modulated by interfaces and applications in biophysics.