Having osteoarthritis in one knee is reported as an independent risk factor for developing contralateral knee osteoarthritis (KOA). However, no study has been designed to predict the development of contralateral KOA (cKOA). The authors hypothesized that specific risk factors for cKOA development exist and that it could be accurately predicted with the assistance of machine learning. KOA was defined using the Kellgren-Lawrence grade (KLG) of 2 or higher. Data from 1353 unilateral KOA patients (900 from the Osteoarthritis Initiative [OAI] and 453 from the Multicenter Osteoarthritis Study [MOST]) over 4–5 years of follow-up were examined. The risk factors for cKOA development were analyzed, and a machine learning model was developed to predict cKOA using OAI as the development data set and MOST as the test data set. cKOA developed in 172 (19.1%) and 178 (39.3%) of the patients (OAI and MOST, respectively) over a period of 4–5 years. A machine learning model was developed using the Tree-based Pipeline Optimization Tool algorithm. This model utilized nine variables, including baseline lateral joint space narrowing grade of the contralateral knee (odds ratio 4.475). The area under the curve of the receiver operating characteristics curve, along with accuracy, precision, and F1-score, were recorded as 0.69, 0.60, 0.50, and 0.58, respectively, in the test data set. The development of cKOA could be effectively predicted using a limited number of variables through machine learning. Surgeons should consider the development of cKOA in patients with identified risk factors when managing KOA patients.