Background: Designing and implementing team interventions to improve quality and safety of care in acute hospital contexts is challenging. There is little emphasis in the literature on how contextual conditions impact interventions or how specific active ingredients of interventions impact on team members’ reasoning and enact change. This realist evaluation helps to deepen the understanding of the enablers and barriers for effective team interventions in these contexts. Methods: Five previously developed initial programme theories were tested using case studies from two diverse hospital contexts. Data were collected from theory driven interviews (n = 19) in an Irish context and from previously conducted evaluative interviews (n = 16) in a US context. Data were explored to unpack the underlying social and psychological drivers that drove both intended and unintended outcomes. Patterns of regularity were identified and synthesised to develop middle-range theories (MRTs). Results: Eleven MRTs demonstrate how and why intervention resources introduced in specific contextual conditions enact reasoning mechanisms and generate intended and unintended outcomes for patients, team members, the team and organisational leaders. The triggered mechanisms relate to shared mental models; openness, inclusivity and connectedness; leadership and engagement; social identity and intrinsic motivational factors. Conclusions: The findings provide valuable information for architects and facilitators of team interventions in acute hospital contexts, as well as help identify avenues for future research. Dataset: The data presented in this study are available on request from the corresponding author. The data are not publicly available due to their sensitive nature and potential identification of participants.