The 5-hydroxytryptamine receptor 6 (5-HT6) has gained attention as a target for developing therapeutics for Alzheimer’s disease, schizophrenia, cognitive dysfunctions, anxiety, and depression, to list a few. In the present analysis, a larger and diverse dataset of 1278 molecules covering a broad chemical and activity space was used to identify visual and concealed structural features associated with binding affinity for 5-HT6. For this, quantitative structure–activity relationships (QSAR) and molecular docking analyses were executed. This led to the development of a statistically robust QSAR model with a balance of excellent predictivity (R2tr = 0.78, R2ex = 0.77), the identification of unreported aspects of known features, and also novel mechanistic interpretations. Molecular docking and QSAR provided similar as well as complementary results. The present analysis indicates that the partial charges on ring carbons present within four bonds from a sulfur atom, the occurrence of sp3-hybridized carbon atoms bonded with donor atoms, and a conditional occurrence of lipophilic atoms/groups from nitrogen atoms, which are prominent but unreported pharmacophores that should be considered while optimizing a molecule for 5-HT6. Thus, the present analysis led to identification of some novel unreported structural features that govern the binding affinity of a molecule. The results could be beneficial in optimizing the molecules for 5-HT6.