Aims. Accurate identification of the ankle joint centre is critical for estimating tibial coronal alignment in total knee arthroplasty (TKA). The purpose of the current study was to leverage artificial intelligence (AI) to determine the accuracy and effect of using different radiological anatomical landmarks to quantify mechanical alignment in relation to a traditionally defined radiological ankle centre. Methods. Patients with full-limb radiographs from the Osteoarthritis Initiative were included. A sub-cohort of 250 radiographs were annotated for landmarks relevant to knee alignment and used to train a deep learning (U-Net) workflow for angle calculation on the entire database. The radiological ankle centre was defined as the midpoint of the superior talus edge/tibial plafond. Knee alignment (hip-knee-ankle angle) was compared against 1) midpoint of the most prominent malleoli points, 2) midpoint of the soft-tissue overlying malleoli, and 3) midpoint of the soft-tissue sulcus above the malleoli. Results. A total of 932 bilateral full-limb radiographs (1,864 knees) were measured at a rate of 20.63 seconds/image. The knee alignment using the radiological ankle centre was accurate against ground truth radiologist measurements (inter-class correlation coefficient (ICC) = 0.99 (0.98 to 0.99)). Compared to the radiological ankle centre, the mean midpoint of the malleoli was 2.3 mm (SD 1.3) lateral and 5.2 mm (SD 2.4) distal, shifting alignment by 0.34. o. (SD 2.4. o. ) valgus, whereas the midpoint of the soft-tissue sulcus was 4.69 mm (SD 3.55) lateral and 32.4 mm (SD 12.4) proximal, shifting alignment by 0.65. o. (SD 0.55. o. ) valgus. On the intermalleolar line, measuring a point at 46% (SD 2%) of the intermalleolar width from the medial malleoli (2.38 mm medial adjustment from midpoint) resulted in knee alignment identical to using the radiological ankle centre. Conclusion. The current study leveraged AI to create a consistent and objective model that can estimate patient-specific adjustments necessary for optimal landmark usage in extramedullary and computer-guided navigation for tibial coronal alignment to match radiological planning. Cite this article: Bone Jt Open 2022;3(10):767–776