Purpose: This study aimed to evaluate the efficacy of the Chat Generative Pre-trained Transformer (ChatGPT) in guiding the need for invasive coronary angiography (ICA) in high-risk non-ST-elevation (NSTE) acute coronary syndrome (ACS) patients based on both standard clinical data and coronary computed tomography angiography (CCTA) findings. Methods: This investigation is a sub-study of a larger prospective multicentric double blinded project where high-risk NSTE-ACS patients underwent CCTA prior to ICA to compare coronary lesion by both modalities. ChatGPT analyzed clinical vignettes containing patient data, electrocardiograms, troponin levels, and CCTA results to determine the necessity of ICA. The AI’s recommendations were then compared to actual ICA findings to assess its decision-making accuracy. Results: In total, 86 patients (age: 62 ± 13 years old, female 27%) were included. ChatGPT recommended against ICA for 19 patients, 16 of whom indeed had no significant findings. For 67 patients, ChatGPT advised proceeding with ICA, and a significant lesion was confirmed in 58 of them. Consequently, ChatGPT’s overall accuracy stood at 86%, with a sensitivity of 95% (95% confidence interval (CI) 0.76–0.92) and a specificity of 64% (95% CI 0.62–0.94). The model’s negative predictive value was 84% (95% CI 0.44–0.79), and its positive predictive value was 87% 95% CI 0.86–0.97). Conclusion: Preliminary evidence suggests that ChatGPT can effectively assist in making ICA decisions for high-risk NSTE-ACS patients, potentially reducing unnecessary procedures. However, the study underscores the importance of data accuracy and calls for larger, more diverse investigations to refine artificial intelligence’s role in clinical decision-making.