Two Schiff bases 2-amino-N'-(5-bromo-2-hydroxybenzylidene)-3-(4-hydroxyphenyl)propanehydrazide (H2L1) and 2-amino-N'-(5-chloro-2-hydroxybenzylidene)-3-(4-hydroxyphenyl)propanehydrazide (H2L2) and their six diorganotin(IV) complexes (R = C4H9 (1, 4), CH3 (2, 5), and C8H17 (3, 6)) have been synthesized. Schiff bases (H2L1-2) and their R2SnL1-2 complexes (1–6) have been characterized by CHNS analysis, IR spectroscopy, 1H, 13C, 119Sn NMR, and ES-MS. Schiff bases (H2L1-2) act as a dianionic tridentate ligand coordinated to Sn through phenolic and enolic oxygen and azomethine nitrogen in R2SnL1-2 complexes (1–6). A density functional theory (DFT)-based quantum chemical calculation validated the structures of R2SnL1 (1–3) and R2SnL2 (4–6) at the B3LYP/6‐311G(df,pd)/Def2‐SVP(Sn) and B3LYP/6‐31G(d,p)/Def2‐SVP(Sn) levels of theory, respectively. At these levels of theories, comprehensive electronic structure calculations determined atomic charges at selected atoms. Additionally, a molecular electrostatic potential (MEP) map identified electrostatic potential-varying sites on the molecule's surface, and MEP maps used to identify regions where other molecules might interact or react with the molecules on them. Furthermore, a conceptual-DFT-based global reactivity descriptor determined the stability and reactivity behaviour of R2SnL1-2 complexes (1–6). H2L1-2 and R2SnL1-2 complexes (1–6) have binding constants in the range ∼105 with CT-DNA, as revealed by UV-visible and fluorescence spectral titrations. UV-visible, fluorescence spectroscopy, and CD studies suggested that H2L1-2 and their R2SnL1-2 complexes (1–6) interact with CT-DNA electrostatically or groove-bound. DNA cleavage studies reveal that H2L1-2 and their R2SnL1-2 complexes (1–6) have ability to cleave the plasmid-DNA from its supercoiled form (SC, I) to nicked form (NC, II). However, n-Bu2SnL2 (4) and n-Oct2SnL2 complex (6) have higher cleavage activity than Schiff bases and other R2SnL1-2 complexes.