Birch plywood has superior mechanical properties compared with that made from most softwoods. However, durability-related issues still limit the application of birch plywood in outdoor structures. A means to enhance its durability is to acetylate birch veneers before processing them into plywood. An earlier study showed that such acetylated birch plywood has equivalent mechanical properties to unmodified ones. However, there is a need to better understand the moisture effect on the mechanical properties of unmodified and acetylated birch plywood for a better design of structural birch plywood elements. Moreover, due to the pronounced in-plane anisotropy of plywood, extra concern should be given to the weakest load angle due to the weakest chain theory. In this study, acetylated and unmodified birch plywood specimens were conditioned in climate chambers under three different environments with a temperature of 20 °C and increasing relative humidity (RH) from 35 to 65% to 95%. Thereafter, their in-plane edgewise flexural properties with load-to-face grain angles of 0, 45, and 90 degrees were tested. The influence of both RH and measured moisture contents on bending strength and stiffness are then presented. Prediction formulas of mechanical properties with moisture contents are derived by performing linear regressions among test results. Variations of brittleness factors and brittleness indexes under various RH conditions and load-face grain angles were also studied.