In cell-material interactions, the formation and functioning of filopodia have been demonstrated to be very sensitive to topographic cues. However, substrate-exploring functions of filopodia in a 3D microenvironment remain elusive. In this study, the silk fibroin film with a micropillar structure was prepared to reveal a filopodial-mediated cell response to 3D topographic cues. The micropillars provided a confined space for cell spreading by a simplified 3D structure, allowing initial cells to settle on the bottom of substrates rather than on the top of micropillars. Shortly after cell adhesion, the authors describe how cells transform from a filopodia-rich spherical cell state to a lamellipodia-dominated state that enables cell to climb along micropillars and spread on the top of the micropillars. The authors found that filopodia not only served as sensors for pathfinding but also provided nucleation scaffolds for the formation and orientation of minilamellipodia on the micropillar substrate. On the route of long filopodial extension following micropillars, all three functional filopodial adhesions have the ability to form veil-like minilamellipodium, simply by tethering the filopodium to the micropillars. Stable filopodia contacts consistently stimulated the local protrusion of a lamellipodium, which ultimately steered cell migration. Their results suggest the filopodia-mediated cell locomotion in the 3D microenvironment using a filopodia-to-minilamellipodium transformation mechanism.