Benchmarking is an important step in the improvement, assessment, and comparison of the performance of drug discovery platforms and technologies. We revised the existing benchmarking protocols in our Computational Analysis of Novel Drug Opportunities (CANDO) multiscale therapeutic discovery platform to improve utility and performance. We optimized multiple parameters used in drug candidate prediction and assessment with these updated benchmarking protocols. CANDO ranked 7.4% of known drugs in the top 10 compounds for their respective diseases/indications based on drug-indication associations/mappings obtained from the Comparative Toxicogenomics Database (CTD) using these optimized parameters. This increased to 12.1% when drug-indication mappings were obtained from the Therapeutic Targets Database. Performance on an indication was weakly correlated (Spearman correlation coefficient _>_0.3) with indication size (number of drugs associated with an indication) and moderately correlated (correlation coefficient _>_0.5) with compound chemical similarity. There was also moderate correlation between our new and original benchmarking protocols when assessing performance per indication using each protocol. Benchmarking results were also dependent on the source of the drug-indication mapping used: a higher proportion of indication-associated drugs were recalled in the top 100 compounds when using the Therapeutic Targets Database (TTD), which only includes FDA-approved drug-indication associations (in contrast to the CTD, which includes associations drawn from the literature). We also created compbench, a publicly available head-to-head benchmarking protocol that allows consistent assessment and comparison of different drug discovery platforms. Using this protocol, we compared two pipelines for drug repurposing within CANDO; our primary pipeline outperformed another similarity-based pipeline still in development that clusters signatures based on their associated Gene Ontology terms. Our study sets a precedent for the complete, comprehensive, and comparable benchmarking of drug discovery platforms, resulting in more accurate drug candidate predictions.