A group of hydrazide and semicarbazide derivatives containing isopropylidene, benzylidene, cyclohexylidene, and phospholidene groups was synthesized and characterized by spectroscopic techniques. These compounds were tested for DNA interaction studies monitored by UV-Vis and IR data as well as molecular docking. Investigations on interactions of these compounds with DNA revealed an intercalative mode of binding between them. It is interesting to note that semicarbazide derivatives with aliphatic substituents showed better DNA binding than the aromatic substituents.