We report results of a study to evaluate effectiveness of a mechanical tissue optical clearing device (TOCD) using optical coherence tomography (OCT). The TOCD uses a pin array and vacuum pressure source to compress localized regions of the skin surface. OCT images (850 and ) of in vivo human skin indicate application of the TOCD provides an up to threefold increased light penetration depth at spatial positions correlated with pin indentations. Increased contrast of the epidermal–dermal junction in OCT images spatially correlates with indented zones. OCT M-scans recorded while applying the TOCD indicate optical penetration depth monotonically increased, with most improvement at early times of TOCD vacuum application. OCT M-scans of ex vivo porcine skin compressed using the TOCD suggest average group refractive index of the tissue increased, corresponding to a decrease in water concentration. Results of our study indicate that mechanical optical clearing of skin may provide an effective and efficient means to deliver increased light fluence to dermal and subdermal regions.