Promoting high-achieving students plays an important role in the school context. Hence, one promising support measure within the mixed-ability classroom is differentiated instruction (DI). The current systematic review examined (1) the impact of DI on high-achieving students' outcomes, (2) to what extent DI is used, (3) how useful teachers and high-achieving students perceive DI, and (4) which barriers and facilitators are encountered in DI's implementation. Forty-nine studies from 2000 to 2019 were included. Differentiated instruction impacted high-achieving students' academic achievement and motivational-affective characteristics predominantly positive. However, there was considerable heterogeneity between and within studies. Teachers typically did not use DI for high-achieving students proactively nor on a regular basis. However, teachers and high-achieving students perceived DI as valuable for encouraging high-achieving students. The barriers found might help to explain discrepancies between the extent of usage and the perceived utility, whereas the identified facilitators suggest how to overcome these barriers.