This study aimed to optimize manufacturing conditions when utilizing eastern white cedar (Thuja occidentalis L.) to increase the durability of structural panels with aspen (Populus tremuloides Michx.) strands in terms of resistance to mold and decay. Panels of three layers using eastern white cedar strands in two face layers and aspen in a core layer were made under different species ratios, temperatures, and pressing conditions. The physical and mechanical properties as well as mold and decay resistances of the panels were tested according to standard methods. Panels with white cedar strands in surfaces and aspen strands in the core at a ratio of 25:50:25 and pressed at 240°C for 180 seconds had the best mechanical and physical properties. Aspen panels with white cedar strands in surfaces at a ratio of 15:70:15 had similar internal bond (IB) and thickness swelling values, lower water absorption (WA), and higher modulus of rupture (MOR) and modulus of elasticity (MOE) compared with pure-aspen control panels. When the white cedar strand proportion in the two surface layers was increased from 15 to 25 percent, IB strength and WA of panels decreased, whereas MOR and MOE increased. Panels with white cedar strands in surfaces at a ratio of 15:70:15 had little infection from molds on the two surface layers but a moderate infection rate on all four sides. In terms of mold and decay resistance, panels made with 25 percent white cedar strands in surfaces performed better than those with 15 percent.