Change of relative humidity (RH) in surrounding environment can greatly affect the physical and mechanical properties of wood-based panels. Commercially produced acetylated medium density fiberboard (MDF), Medite Tricoya®, was used in this study to predict strength and stiffness under varying humid conditions by separating samples in parallel (//) and perpendicular (⊥) to the sanding directions. Thickness swelling, static moduli of elasticity (MOEstat) and rupture (MORstat), and internal bond (IB) strength were measured at three different humid conditions, i.e., dry (35% RH), standard (65% RH) and wet (85% RH). Internal bond (IB) strength was also measured after accelerated aging test. A resonance method was used to determine dynamic modulus of elasticity (MOEdyn) at the aforementioned humid conditions. Linear regression and finite element (FE) analyses were used to predict the MDF’s static bending behavior. Results showed that dimensional stability, MOEstat, MORstat and IB strength decreased significantly with an increase in RH. No reduction of IB strength was observed after 426 h of accelerated aging test. A multiple regression model was established using MOEdyn and RH values to predict MOEstat and MORstat. In both directions (// and ⊥), highly significant relationships were observed. The predicted and the measured values of MOEstat and MORstat were satisfactorily related to each other, which indicated that the developed model can be effectively used for evaluating the strength and stiffness of Medite Tricoya® MDF samples at any humid condition. Percent errors of two different simulation techniques (standard and extended FE method) showed highly efficient way of simulating the MDF structures with low fidelity.