The electro-mechanical brake is a new advancement in railway train braking. Ball-screws are important components of electro-mechanical braking units (EMBUs), and their wear can cause EMBUs to degrade in performance or even fail to function. In this paper, we present a framework for prediction of ball-screw wear with discrete operating conditions as inputs, taking into account the time-varying characteristics of EMBUs. The framework includes determining the contact type, analyzing relative motion, calculating contact deformations, and estimating wear. The contact type is determined based on the quasi-static approach of Hertz theory. A dynamics model using multiple coordinate systems is established to analyze how balls and raceways move in relation to each other. The contact deformations of the ball–raceway contact are determined using numerical calculation. Then, the wear depth increment is calculated using the Archard model. The results of the calculation and the endurance test indicate that the wear on the screw raceway is greater than that on the nut raceway. The effect of velocity is greater than the effect of axial force. The presented calculation framework is reasonable and can be used for predicting EMBU ball-screw wear.