We demonstrate how substrate interfacial chemistry can be utilized to tailor the physical properties of single-crystalline molybdenum disulfide (MoS₂) atomic-layers. Semiconducting, two-dimensional MoS₂ possesses unique properties that are promising for future optical and electrical applications for which the ability to tune its physical properties is essential. We use self-assembled monolayers with a variety of end termination chemistries to functionalize substrates and systematically study their influence on the physical properties of MoS₂. Using electrical transport measurements, temperature-dependent photoluminescence spectroscopy, and empirical and first-principles calculations, we explore the possible mechanisms involved. Our data shows that combined interface-related effects of charge transfer, built-in molecular polarities, varied densities of defects, and remote interfacial phonons strongly modify the electrical and optical properties of MoS₂. These findings can be used to effectively enhance or modulate the conductivity, field-effect mobility, and photoluminescence in MoS₂ monolayers, illustrating an approach for local and universal property modulations in two-dimensional atomic-layers.