Background: Mitral valve regurgitation (MR) is the most common valvular heart disease and current variables associated with MR recurrence are still controversial. We aim to develop a machine learning-based prognostic model to predict causes of mitral valve (MV) repair failure and MR recurrence. Methods: 1000 patients who underwent MV repair at our institution between 2008 and 2018 were enrolled. Patients were followed longitudinally for up to three years. Clinical and echocardiographic data were included in the analysis. Endpoints were MV repair surgical failure with consequent MV replacement or moderate/severe MR (>2+) recurrence at one-month and moderate/severe MR recurrence after three years. Results: 817 patients (DS1) had an echocardiographic examination at one-month while 295 (DS2) also had one at three years. Data were randomly divided into training (DS1: n = 654; DS2: n = 206) and validation (DS1: n = 164; DS2 n = 89) cohorts. For intra-operative or early MV repair failure assessment, the best area under the curve (AUC) was 0.75 and the complexity of mitral valve prolapse was the main predictor. In predicting moderate/severe recurrent MR at three years, the best AUC was 0.92 and residual MR at six months was the most important predictor. Conclusions: Machine learning algorithms may improve prognosis after MV repair procedure, thus improving indications for correct candidate selection for MV surgical repair.