The goal of aptitude-treatment interactions (ATIs) is to find the interactions between treatments and learners’ aptitudes and therefore to achieve optimal learning. This study aimed at understanding whether the aptitudes of meaning-making, self-regulation, and knowledge management (KM) would interact with the treatment of 17- week KM-based training and then influence creativity in e-learning. The participants were 31 university students, and all variables were measured using online systems. ATIs and mediation effects during the training were found. Specifically, while meaning-making indirectly influenced creativity via KM, self-regulation influenced creativity both directly and indirectly via KM; moreover, university students with higher level of KM and selfregulation ability benefited more from the training than their counterparts. This study not only sheds lights on understanding how ATIs influence creativity learning, but also provides a new approach—KM-based training—to improve university students’ creativity in environments of e-learning.