Three quantitative structure-activity relationship (QSAR) models for predicting the affinity of mu-opioid receptor (OR) ligands have been developed. The resulted models, exploiting the accessibility of the QSAR modeling, generate a useful tool for the investigation and identification of unclassified fentanyl-like structures. The models have been built using a set of 115 molecules using Forge as a software, and the quality was confirmed by statistical analysis, resulting in being effective for their predictive and descriptive capabilities. The three different approaches were then combined to produce a consensus model and were exploited to explore the chemical landscape of 3000 fentanyl-like structures, generated by a theoretical scaffold-hopping approach. The findings of this study should facilitate the identification and classification of new OR ligands with fentanyl-like structures.