Skin optical clearing has shown tremendous potential in improving various optical imaging performances, but there is some certain blindness in screening out high-efficiency in vivo optical clearing methods. In this work, three optical clearing agents: sucrose (Suc), fructose (Fruc) and PEG-400 (PEG), and two chemical penetration enhancers: propylene glycol (PG) and thiazone (Thiaz) were used. PEG was firstly mixed with the two penetration enhancers, respectively, and then mixed with Fruc and Suc, respectively, to obtain six kinds of skin optical clearing agents (SOCAs). Optical coherence tomography angiography was applied to monitor SOCAs-induced changes in imaging performances, skin optical properties, refractive index mismatching extent, and permeability rate. Experimental results demonstrated that PEG+Thiaz+Suc has the optimal capacity in enhancing the imaging performances, decreasing the scattering and the refractive index mismatching since Thiaz is superior to PG, and Suc is superior to Fruc. This study indicates that the optimal SOCA can be obtained directly by means of additionally adding or replacing the similar category substance in preexisting SOCAs with some more effective reagents. It not only provides an optimal SOCA, but also provides a useful way to develop more effective SOCAs. Cross-section skin structural texture (a), reconstructed blood flow distribution information (b), before or after treated with different SOCAs.