Molecular docking procedure is well known for the investigation of small molecules; however, for macromolecules, it has attained limited success so far. Thus, in an attempt, a series of poly (azomethine) esters was synthesized in a laboratory, and their model oligomer units were studied by computer-aided computational MOE software package to investigate, specifically, binding modes that could influence their anticancer activities. Poly (azomethine) ester (PAME) was prepared by solution phase polycondensation of a preformed Schiff base (SB) 4-((4-(4-(4-hydroxybenzylideneamino)phenoxy)phenylimino)methyl) phenol with terephthaloyl chloride (TC). Terpolymers (PAMEF, PAMEB, PAMESi, PAMEPr, and PAMEH) were synthesized by the incorporation of various moieties along with TC and SB in the main chain. Structural elucidation was carried out by spectroscopic studies and elemental analysis. Docking procedure, adopted to investigate anticancer activity, showed that material was docked in the same pocket of active site as by anticancer protein complex (PDB code: 1T69). Molecular docking along with the quantitative structure activity relationship (QSAR) investigations showed groove binding as a preferred mode between the material and double-stranded DNA (PDB ID-1BNA). Binding strength indicated worthy correlation with various physicochemical parameters of the material like hydrophobic surface area (Vsurf), EHOMO, ELUMO, log P, and molar refractivity (MR). Calculated values for the formation constant (Kf) showed good binding strength for polymer-DNA complex. Consequently, the synthesized material is expected to exhibit anticancer activities and could be studied further as anticancer drugs.