Surface-degrading polymers have been widely used to fabricate scaffolds with the mechanical properties appropriate for tissue regeneration/repair. During their surface degradation, the material properties of polymers remain approximately unchanged, but the scaffold geometry and thus mechanical properties vary with time. This paper presents a novel method to determine the time-dependent mechanical properties, particularly stiffness, of scaffolds from the geometric changes captured by synchrotron-based imaging, with the help of finite element analysis (FEA). Three-dimensional (3D) tissue scaffolds were fabricated from surface-degrading polymers, and during their degradation, the tissue scaffolds were imaged via the synchrotron-based imaging to characterize their changing geometry. On this basis, the stiffness behavior of scaffolds was estimated from the FEA, and the results obtained were compared to the direct measurements of scaffold stiffness from the load–displacement material testing. The comparison illustrates that the Young's moduli estimated from the FEA and characterized geometry are in agreement with the ones of direct measurements. The developed method of estimating the mechanical behavior was also demonstrated effective with a nondegrading scaffold that displays the nonlinear stress–strain behavior. The in vivo monitoring of Young's modulus by morphology characterization also suggests the feasibility of characterizing experimentally the difference between in vivo and in vitro surface degradation of tissue engineering constructs.