We present an in silico drug discovery pipeline developed and applied for the identification and virtual screening of small-molecule Protein-Protein Interaction (PPI) compounds that act as dual inhibitors of TNF and RANKL through the trimerization interface. The cheminformatics part of the pipeline was developed by combining structure–based with ligand–based modeling using the largest available set of known TNF inhibitors in the literature (2481 small molecules). To facilitate virtual screening, the consensus predictive model was made freely available at: http://enalos.insilicotox.com/TNFPubChem/. We thus generated a priority list of nine small molecules as candidates for direct TNF function inhibition. In vitro evaluation of these compounds led to the selection of two small molecules that act as potent direct inhibitors of TNF function, with IC₅₀ values comparable to those of a previously-described direct inhibitor (SPD304), but with significantly reduced toxicity. These molecules were also identified as RANKL inhibitors and validated in vitro with respect to this second functionality. Direct binding of the two compounds was confirmed both for TNF and RANKL, as well as their ability to inhibit the biologically-active trimer forms. Molecular dynamics calculations were also carried out for the two small molecules in each protein to offer additional insight into the interactions that govern TNF and RANKL complex formation. To our knowledge, these compounds, namely T8 and T23, constitute the second and third published examples of dual small-molecule direct function inhibitors of TNF and RANKL, and could serve as lead compounds for the development of novel treatments for inflammatory and autoimmune diseases. Developing drugs that disrupt protein-protein interactions (PPIs) is a difficult task in pharmaceutical research. The interaction between protein Tumor Necrosis Factor (TNF) and its receptors is implicated in several physiological functions and diseases, such as rheumatoid and psoriatic arthritis, Crohn’s disease, and multiple sclerosis. Despite their potency, current medications that block the interaction between TNF and its receptors are also associated with many adverse functions. Here, we employ comprehensive computational and experimental methods to discover novel small molecules that are direct inhibitors of TNF function. Functionality for RANKL, a second, clinically-relevant member of the TNF protein family, was also examined. Using a combination of an in silico drug discovery pipeline, which includes structure- and ligand-based modeling, and in vitro experiments, we identified compounds T8 and T23 as dual inhibitors of TNF and RANKL. These compounds present low toxicity and may be further optimized in drug design targeting TNF and RANKL to develop improved treatments for a range of inflammatory and autoimmune diseases.