Background The rapid development of artificial intelligence has permeated many fields, with its application in drug discovery becoming increasingly mature. Machine learning, particularly deep learning, has significantly improved the efficiency of drug discovery. In the core task of predicting drug–target affinity (DTA), deep learning enhances predictive performance by automatically extracting complex features from compounds and proteins. Methods Traditional approaches often rely heavily on sequence and two-dimensional structural information, overlooking critical three-dimensional and physicochemical properties. To address this, we propose a novel model—Cross Attention Fusion based on Information Enhancement for Drug–Target Affinity Prediction (CAFIE-DTA)—which incorporates protein 3D curvature and electrostatic potential information. The model approximates protein surface curvature using Delaunay triangulation, calculates total electrostatic potential via Adaptive Poisson-Boltzmann Solver (APBS) software, and employs cross multi-head attention to fuse physicochemical and sequence information of proteins. Simultaneously, it integrates graph-based and physicochemical features of compounds using the same attention mechanism. The resulting protein and compound vectors are concatenated for affinity prediction. Results Cross-validation and comparative evaluations on the benchmark Davis and KIBA datasets demonstrate that CAFIE-DTA outperforms existing methods. On the Davis dataset, it achieved improvements of 0.003 in confidence interval (CI) and 0.022 in R2. On the KIBA dataset, it improved MSE by 0.008, CI by 0.005, and R2 by 0.017. Compared to traditional models relying on 2D structures and sequence data, CAFIE-DTA shows superior performance in DTA prediction. The source code is available at: https://github.com/NTU-MedAI/CAFIE-DTA.