We have investigated at the theoretical Density Functional Theory level the way the work function of zinc oxide layers is affected upon deposition of self-assembled monolayers (SAMs). 4-tert-Butylpyridine (4TBP) and various benzoic acids (BA) were adsorbed on the apolar (100) ZnO and used as probe systems to assess the influence of several molecular parameters. For the benzoid acids, we have investigated the impact of changing the nature of the terminal group (H, CN, OCH₃) and the binding mode of the carboxylic acid (monodentate versus bidentate) on the apolar (100) surface. For each system, we have quantified the contribution from the molecular core and the anchoring group as well as of the degree of surface reconstruction on the work function shift. For the benzoic acids, the structural reorganization of the surface induces a negative shift of the work function by about 0.3 ± 0.15 eV depending on the nature of the binding mode, irrespective of the nature of the terminal function. The bond-dipole potential strongly contributes to the modification of the work function, with values in the range +1.2 to +2.0 eV. In the case of 4TBP, we further characterized the influence of the degree of coverage and of co-adsorbed species (H, OH, and water molecules) on the ZnO/SAM electronic properties as well as the influence of the ZnO surface polarity by considering several models of the polar (0001) ZnO surface. The introduction of water molecules in the (un)dissociated form at full coverage on the non-polar surface only reduces the work function by 0.3–0.4 eV compared to a reference system without co-adsorbed species. Regarding the polar surface, the work function is also significantly reduced upon deposition of a single 4BTP molecule (from −1.44 eV to −1.73 eV for our model structures), with a shift similar in direction and magnitude compared to the non-polar surfaces.