The aim of this paper is to identify the opportunities and challenges of innovation programs, discuss and analyse the adaptation of the innovation program in the United States (US) and United Kingdom (UK). To achieve the aim, the research used a mixed-methods approach quantitative (survey) and qualitative (multi-case study) to examine innovation best practices in developed countries. In addition, the selection of 4 interview case studies of innovation organisations based on the best practices and successful implementation worldwide. The research findings indicated the two challenges such as 1) innovation required globalisation for transformation of the new product and new services, and 2) strengthen the climate of entrepreneurship as a vital component in the innovation programs. Although the two opportunities such as 1) sustainability of the technology to lead smart growth, and 2) strengthen the platforms for entrepreneurship networking at multi-levels. The research adds value to academicians and practitioners such as government, funded organizations, institutions, and policymakers.