Background: In 2022, England embarked on an ambitious and innovative re-organisation to produce an integrated health and care system with a greater focus on improving population health. This study aimed to understand how nascent ICSs are developing and to identify the key challenges and enablers to integration. Methods: Four ICSs participated in the study between November 2021 and May 2022. Semi-structured interviews with system leaders (n = 67) from health, social and voluntary care as well as representatives of local communities were held. A thematic framework approach supported by Leutz’s five laws of integration framework was used to analyse the data. Results: The benefits of ICSs include enhancing the delivery of good quality care, improving population health and providing more person-centred care in the community. However, differences between health and social care such as accountability, organisational/professional cultures, risks of duplicating efforts, tensions over funding allocation, issues of data integration and struggles in engaging local communities threaten to hamper integration. Conclusions: Despite ICS’s investing in the structural and relational components of integrated care, the unprecedented pressures on systems to reduce demand on primary and emergency care tackling elective backlogs may detract from a key goal of ICSs, improving population health and prevention.