Quantitative structure–activity relationship modeling of 4-anilinofuro[2,3-b]quinoline derivatives have been subjected in the current study utilizing theoretical molecular descriptors calculated solely from the structures of chemical compounds. This study explored the influences of electrostatic, topological, constitutional, geometrical, and physicochemical descriptors toward antimitotic activities of these compounds. Stepwise forward–backward-based feature selection coupled with partial least squares was used as a chemometric tool for QSAR modeling. The training models were properly validated and focused regarding the different structural aspects necessary for designing potent compounds in these series. Further in vitro absorption and distribution were studied using PreADMET algorithm for these series of compounds to predict important structural requirements. More hydrophilic of these congeneric compounds potentiate antimitotic activity. O-substituted dimethyl aminoalkyl oxime moiety makes the compound more hydrophilic and free for interaction with the mitotic spindle. Predictive absorption and distribution study through Caco-2 cell permeability and plasma protein binding (%) help to design more active antimitotic compounds in this congeners.