This study evaluated the mechanical properties of hybrid (mixed-species) cross-laminated timber (CLT) panels made of low-value sugar maple (Acer saccharum) and white spruce (Picea glauca). The modulus of elasticity (MOE) of the laminations was measured with a nondestructive method. Three-layer hybrid CLT panels with layup combinations of sugar maple–white spruce–sugar maple and white spruce–sugar maple–white spruce were prepared to evaluate the effects of layups on the performance of the CLT samples. The mechanical properties of hybrid CLT panels were evaluated with different layups and both melamine- and resorcinol-based adhesives. Both long-span and short-span third-point bending tests were conducted to study the flexural and shear behavior of each CLT panel type. It was found that the influence of adhesive types was not significant. The mechanical properties of the hybrid CLT panels with sugar maple surface layers were improved significantly compared with those of the current standard layups. Both bending tests were simulated with finite-element analysis based on measured and reference material properties. The simulated results of each case were in good agreement with the test results.