Biomaterials’ surface properties elicit diverse cellular responses in biomedical and biotechnological applications. Predicting cell behaviour on polymeric surface is an ongoing challenge due to its complexity. This work proposes a novel modelling methodology based on attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy. Spectra were collected on wetted polymeric surfaces to incorporate both surface chemistry and information on water-polymer interactions. The best model was seen to predict total area of focal adhesions (FAs) with coefficient of determination for prediction (〖R^2〗_P) of 0.94 and root mean square errors of prediction (RMSEP) of 2.57 µm when tested on an independent experimental set. This work offers new insights into our understanding of cell-biomaterial interactions. The presence of carboxyl groups in polymers promoted larger adhesion areas, yet the formation of carbonyl-to-water interaction decreased adhesion areas. Surface wettability, which was related to water-polymer interaction, was proven to highly influence cell adhesion.