Contrasting behavior of Nonsteroidal anti-inflammatory drug Sulindac (SDC) towards two different proteins Human hemoglobin (HHb) and Lysozyme (LYS) has been explored by multispectroscopy, molecular docking, DFT and MD Simulation approaches. The fluorescence quenching experiments showed that SDC strongly binds with both proteins in a static manner. Alteration in the secondary structure of HHb and LYS in presence of SDC was further investigated by CD and UV–visible spectroscopy. It is observed that on addition of SDC, the % α-helix of native HHb decreases whereas it increases for LYS-SDC system substantiated the fact SDC stabilized the secondary structure of LYS and destabilized the HHb structure thus, showing the contrasting traits. Experimental results further validated by computational techniques. Molecular docking and DFT were conducted to study the binding sites, nature of interactions and HOMO-LUMO energy gap in both the systems which revealed that the binding of SDC with both proteins resulted in the considerable change in the molecular structure of the former. Additionally, we performed MD simulations to study the structural stability of Lysozyme and Hemoglobin, both unbound and bound to the Sulindac molecule. Sulindac binding showed distinct impacts on protein stability in both proteins, supported by global and essential dynamics.This study not only provides important insights into the binding of SDC with HHb and LYS but also it provides a useful direction in the pharmacology and clinical medicine fields.