Various methods have been proposed for enhancing the contrast of laser speckle contrast image (LSCI) in subcutaneous blood flow measurements. However, the LSCI still suffers from low image contrast due to tissue turbidity. Herein, a physicochemical tissue optical clearing (PCTOC) method was employed to enhance the contrast of LSCI. Ex vivo and in vivo experiments were performed with porcine skin samples and male ICR mice, respectively. The ex vivo LSCIs were obtained before and 90 min after the application of the PCTOC and in vivo LSCIs were obtained for 60 min after the application of the PCTOC. In order to obtain the skin recovery images, saline was applied for 30 min after the application of the PCTOC was completed. The visible appearance of the tubing under ex vivo samples and the in vivo vasculature gradually enhanced over time. The LSCI increased as a function of time after the application of the PCTOC in both ex vivo and in vivo experiments, and properly recovered to initial conditions after the application of saline in the in vivo experiment. The LSCI combined with the PCTOC was greatly enhanced even in deep vasculature. It is expected that similar results will be obtained in in vivo human studies.