Background: Multiplayer games have emerged as a promising approach to increase the motivation of patients involved in rehabilitation therapy. In this systematic review, we evaluated recent publications in health-related multiplayer games that involved patients with cognitive and/or motor impairments. The aim was to investigate the effect of multiplayer gaming on game experience and game performance in healthy and non-healthy populations in comparison to individual game play. We further discuss the publications within the context of the theory of flow and the challenge point framework. Methods: A systematic search was conducted through EMBASE, Medline, PubMed, Cochrane, CINAHL and PsycINFO. The search was complemented by recent publications in robot-assisted multiplayer neurorehabilitation. The search was restricted to robot-assisted or virtual reality-based training. Results: Thirteen articles met the inclusion criteria. Multiplayer modes used in health-related multiplayer games were: competitive, collaborative and co-active multiplayer modes. Multiplayer modes positively affected game experience in nine studies and game performance in six studies. Two articles reported increased game performance in single-player mode when compared to multiplayer mode. Conclusions: The multiplayer modes of training reviewed improved game experience and game performance compared to single-player modes. However, the methods reviewed were quite heterogeneous and not exhaustive. One important take-away is that adaptation of the game conditions can individualize the difficulty of a game to a player’s skill level in competitive multiplayer games. Robotic assistance and virtual reality can enhance individualization by, for example, adapting the haptic conditions, e.g. by increasing haptic support or by providing haptic resistance. The flow theory and the challenge point framework support these results and are used in this review to frame the idea of adapting players’ game conditions.