The viability of cells and the integrity of the genome depend on the detection and repair of damaged DNA through intricate mechanisms. Cancer treatment employs chemotherapy or radiation therapy to eliminate neoplastic cells by causing substantial damage to their DNA. In many cases, improved DNA repair mechanisms lead to resistance to these medicines; therefore, it is essential to expand efforts to develop drugs that can sensitise cells to these treatments by inhibiting the DNA repair process. Multiple studies have demonstrated a correlation between the overexpression of Apurinic/Apyrimidinic Endonuclease (APE1), the primary mammalian enzyme responsible for excising apurinic or apyrimidinic sites in DNA, and the resistance of cells to cancer therapies; in contrast, APE1 downregulation increases cellular susceptibility to DNA-damaging agents. Thus, the effectiveness of existing therapies can be improved by promoting the targeted sensitization of cancer cells while protecting healthy cells. The current study aims to employ explainable artificial intelligence (XAI) to enhance the accuracy and reliability of machine learning models for the prediction of APE1 inhibitors. Various ML-based regression models are employed to predict the pIC50 value of different medicines. Bayesian optimization and the Permutation Feature Importance (PFI) approach are employed to determine the best hyperparameters of machine learning models and to discover the most significant features for recognizing drug candidates that target APE1 enzymes, respectively. To acquire comprehensive elucidations for the predictive models in our research, two XAI methodologies, namely SHAP and LIME, are used. The SHAP analysis reveals that the features 'C1SP2' and 'ASP-2' are essential in influencing the model's predictions. The SHAP values demonstrate variability for features such as 'maxHBint2' and 'GATS1s,' signifying that their impact is dependent on specific instances within the dataset. The LIME study corroborates these findings, demonstrating that 'C1SP2' and 'ASP-2' are the most significant positive contributors, whereas features like 'SHCHnX,' 'nHdCH2,' and 'GATS1s' result in a decrease in the predicted values. Due to the limited sample size of the APE1 dataset, direct training on this dataset posed challenges in model generalization and reliability. To overcome this limitation, the BACE-1 dataset is leveraged for model training, enabling the ML models to learn from a more extensive and diverse chemical space. Among the tested algorithms, XGBoost demonstrated superior predictive performance, achieving R² = 0.890, MAE = 0.186, and RMSE = 0.245, significantly surpassing state-of-the-art methods, such as LightGBM and QSAR-ML, which attained R² scores of 0.798 and 0.630, respectively. These results highlight the robustness of our approach, demonstrating its enhanced generalization capability and superior predictive accuracy compared to existing methodologies.