The aim of this study was to set the reaction conditions of the photoinduced reforming of glycerol aqueous solution over Pt/hex-CdS under visible light irradiation for enhancement of hydrogen production by using a fractional factorial experimental design followed by a Box–Behnken design. The parameters assessed were irradiation time, mass of photocatalyst, concentration of glycerol, pH and electrolyte concentration (NaCl). The preliminary two-level fractional factorial design (25−1) showed that all of the investigated factors have significant effect in hydrogen production, being pH the most important parameter. The three factors Box–Behnken design showed maximum response for hydrogen production in pH 4.0, 55% glycerol and 1.5 mol L−1 NaCl. The amount of hydrogen obtained under these conditions was 270% higher than our previous result, using the same photocatalyst and electron donor. In the ideal pH, >CdSH2+and >CdOH species are predominant before irradiation, indicating that such species play an important role in the primary steps of the photoelectrochemical mechanism, which served as the basis for proposing a mechanism for hydrogen generation as well as glycerol photooxidation. Based on the surface response [NaCl] × [glycerol], a solution with salinity equivalent to approximately the natural seawater was tested and the result for hydrogen production was comparable to the best condition; besides, under this condition, the solubility of CdS in aqueous solution is reduced.