The research presented in this paper examines the shear resistance performance of self-tapping screws (STS) in three-ply cross-laminated timber (CLT) panels. Specifically, the feasibility of using innovative STS assemblies with double inclination of fasteners was investigated for the shear connection of CLT panels. The specimens (1.5×1.5 m) were subjected to quasi-static and reversed-cyclic loading. The tests were set up to approximate pure shear loading, with three-panel CLT assemblies connected with STS. The resulting load-displacement and hysteretic curves were used to determine an equivalent energy elastic-plastic curve to estimate assembly capacity, yield load, yield displacement, ductility ratio, stiffness, and damping. Excellent structural performance in terms of capacity and stiffness was obtained while still providing the required ductility for the system to be used in seismic applications. The average static and cyclic yield loads were 6.0 kN/screw and 5.9 kN/screw, respectively. Average static and cyclic and ductility ratios were 7.7 and 4.1, respectively, allowing the connection to be classified as highly ductile under quasi-static loading and moderately ductile under reversed cyclic loading. The data obtained allow engineers to specify an innovative connection assembly with double inclination of fasteners for lateral load–resisting systems of CLT structures.