To gain insights into few layer (FL) van der Waals MoO3-xSx/MoS2-xOx heterostructures for photocatalytic applications, we analyze how the concentration (x) and location of anionic isovalent atom (S or O) substitutions impact their opto-electronic properties and high frequency dielectric constant profiles. By using density functional theory (DFT) calculations within the HSE06 functional, we show that the electronic band gap of FL MoO3-xSx decreases with increasing x, while the dielectric constant profile and absorption coefficient in the UV-vis range increase. The stronger band gap reductions are obtained when S-atoms are located in the internal bulk region of FL MoO3-xSx and in interaction with O-atoms of the neighboring layer. Moreover, the conduction and valence band (CB/VB) levels are shifted to higher energy values in the case of the edge location (external surface) of these S-atoms. Thanks to the determination of the thermodynamic diagrams of 4L MoO3-xSx and 6L MoS2-xOx, we propose optimal heterojunctions made of 4L MoO3-xSx with either single-layer (SL) or FL MoS2 with CB/VB levels compatible with a Z-scheme working principle and with potentials required for photocatalysis applications such as the photolysis of water into O2 and H2. This study combined with our previous theoretical investigations on bulk materials and SL provides a thorough analysis of SL-FL MoO3-xSx/MoS2 heterojunctions where the concentration and location of S-atoms in MoO3-xSx are key to design efficient materials for water photolysis.