The sensing of small molecules poses the challenge of developing devices able to discriminate between compounds that may be structurally very similar. Here, attention has been paid to the use of self-assembled monolayer (SAM)-protected gold nanoparticles since they enable a modular approach to tune single-molecule affinity and selectivity simply by changing functional moieties (i.e., covering ligands), along with multivalent molecular recognition. To date, the discovery of monolayers suitable for a specific molecular target has relied on trial-and-error approaches, with ligand chemistry being the main criterion used to modulate selectivity and sensitivity. By using molecular dynamics, we showcase that either individual molecular characteristics and/or collective features such as ligand flexibility, monolayer organization, ligand local ordering, and interfacial solvent properties can also be exploited conveniently. The knowledge of the molecular mechanisms that drive the recognition of small molecules on SAM-covered nanoparticles will critically expand our ability to manipulate and control such supramolecular systems.