A handheld near-infrared imager was developed for real-time monitoring of tissue physiologic changes in response to dynamic compression stimuli. Both 2D and 3D imaging schemas were developed for reconstruction of tissue heterogeneities based on optical measurements. The handheld imager and the dynamic imaging schema were validated on both benchtop phantoms and in vivo human tissues. The benchtop tests demonstrated that the imager was able to reconstruct absorption properties of the embedded heterogeneity with accuracy and repeatability. The tests on in vivo human tissues demonstrated that the imager was able to generate various dynamic loading profiles with reproducibility and to detect tissue optical, mechanical, and physiologic changes under the dynamic loading condition.