Lower limb tissue stiffness is contingent on various factors, including body composition, loading rates, and the geometry of the indenting object. In comparison to more conventional engineering materials, biological soft tissues possess complicated structures that exhibit unique nonlinear mechanical behaviour. Being able to predict the gross mechanical behaviour of human soft tissue under different loading conditions could enable researchers and engineers to improve the performance of biomedical devices through optimized human-device interfaces. In this study, a custom-built handheld indentation device was used to explore changes in leg tissue stiffness at rest and during isometric contractions. Corresponding force-displacement relationships were modelled using a two-parameter exponential growth function. Averaged across 18 subjects and two indentation locations (thigh/shank), deformation forces during activation increased by a factor of ~1.6x over the same displacement as inactive data. Thus, bulk tissue stiffness varies dramatically with underlying muscle activation;​ this should be considered in developing novel orthoses.