Laser micro-drilling was applied to Fe substrates to enhance the interfacial properties of carbon fiber-reinforced polymer/iron laminates. This architecture is referred to as a resin-interlocked Fe-CFRP hybrid composite. Inspired by human hair follicles’ exceptional adhesion and filling efficiency, novel biomimetic frustum-integrated cylindrical cavities were engineered for Fe surface modification. Experimental results demonstrate that laser-processed surfaces with varied hole geometries (conical, conical frustum, cylindrical, and frustum-integrated cylindrical cavities) exhibit significantly improved interfacial performance compared to untreated Fe controls. Specifically, RI-Fe/CFRP specimens containing frustum-integrated cylindrical cavities achieved the highest shear strength, with a 44.8% increase over non-drilled counterparts. Subsequent molecular dynamics simulations confirmed the critical role of the cavity geometry, demonstrating that the frustum-integrated cylindrical cavity elevates the Fe–Diglycidyl ether of bisphenol-A interfacial energy and van der Waals interactions by 45.44% and 50.66%, respectively, versus the flat surface. The interfacial energy enhancement mechanism via distinct hole configurations was systematically studied. Furthermore, comprehensive micro-hole topology analysis elucidated the reinforcement mechanism in resin-interlocked Fe-CFRP hybrid composites. Results demonstrate that frustum-integrated cylindrical cavities significantly enhance DGEBA-3,3′-diaminodiphenyl sulfone fluidity during interface simulation, promoting mechanical interlocking and optimized resin-filling efficiency. Laser micro-drilling effectively improves Fe-DGEBA interfacial performance. These findings provide critical insights for designing high-performance composites in aerospace and automotive applications.