Abstract Aims This study was aimed at investigating whether a machine learning (ML)-based coronary computed tomographic angiography (CCTA) derived fractional flow reserve (CT-FFR) SYNTAX score (SS), ‘Functional SYNTAX score’ (FSSCTA), would predict clinical outcome in patients with three-vessel coronary artery disease (CAD). Methods and results The SS based on CCTA (SSCTA) and ICA (SSICA) were retrospectively collected in 227 consecutive patients with three-vessel CAD. FSSCTA was calculated by combining the anatomical data with functional data derived from a ML-based CT-FFR assessment. The ability of each score system to predict major adverse cardiac events (MACE) was compared. The difference between revascularization strategies directed by the anatomical SS and FSSCTA was also assessed. Two hundred and twenty-seven patients were divided into two groups according to the SSCTA cut-off value of 22. After determining FSSCTA for each patient, 22.9% of patients (52/227) were reclassified to a low-risk group (FSSCTA ≤ 22). In the low- vs. intermediate-to-high (>22) FSSCTA group, MACE occurred in 3.2% (4/125) vs. 34.3% (35/102), respectively (P < 0.001). The independent predictors of MACE were FSSCTA (OR = 1.21, P = 0.001) and diabetes (OR = 2.35, P = 0.048). FSSCTA demonstrated a better predictive accuracy for MACE compared with SSCTA (AUC: 0.81 vs. 0.75, P = 0.01) and SSICA (0.81 vs. 0.75, P < 0.001). After FSSCTA was revealed, 52 patients initially referred for CABG based on SSCTA would have been changed to PCI. Conclusion Recalculating SS by incorporating lesion-specific ischaemia as determined by ML-based CT-FFR is a better predictor of MACE in patients with three-vessel CAD. Additionally, the use of FSSCTA may alter selected revascularization strategies in these patients.