This study has provided a rational approach for the development of new 3,4-dihydro-2H-benzo[1,4]oxazine derivatives as potential 5-HT6 antagonists. The descriptors identified in CP-MLR analysis have highlighted the role of atomic van der Waals volume in terms of BEHv6, path/walk ratio 3 and 4- Randic shape index (PW3 and PW4), number of rotatable bonds (RBN) and superpendentic index (SPI) to explain the biological actions of 3,4-dihydro- 2H-benzo[1,4]oxazine derivatives as potential 5-HT6 antagonists. Applicability domain analysis revealed that the suggested model matches the high quality parameters with good fitting power and the capability of assessing external data and almost all of the compounds was within the applicability domain of the proposed model and were evaluated correctly.