A set of twenty seven compounds - Schiff bases and their derivatives having anticonvulsant activity were subjected to two dimensional quantitative structure activity relationship studies using Discovery Studio 2.1. Various physicochemical descriptors belonging to different categories were calculated by using Calculate Molecular Properties Protocol of the software. QSAR models were built using Genetic Function Approximation Protocol to generate a population of models for establishing correlation between the binding affinity and descriptors. Statistical qualities of the generated models were judged by parameters like regression coefficient (r2), adjusted regression coefficient (r2 adj), cross-validated regression coefficient (r2 cv), F-value and Friedman’s LOF embedded in the software. Logarithmic inverse values of ED50 were taken as dependent variable and descriptors – Total Energy VAMP, Dipole Mag VAMP, Electrostatic hydrogen bond acidity Propgen VAMP, Quadrupole ZZ VAMP, ALogP, HBD_Count and Kappa_3 were taken as independent variables. The best QSAR model (r2 = 0.905972, r2 adj = 0.872391, r2 pred = 0.63, LOF = 0.009644, F = 2.9778) had acceptable statistical quality and predictive potential as indicated by the value of cross validated squared correlation coefficient (r2 cv = 0.808752). This validated model highlighted the important structural requirements for design of anticonvulsant drugs.