The pandemic marked the beginning of a succession of events on a global scale (not the least of which is a greater concern for the environment and for quality of life/distance work) with a major impact on the economy. Innovation plays a key role in meeting the challenges of the future, but despite investment in innovation, global economic growth has fallen short of the expected performance. The aim of this study is to identify the factors with the greatest impact on the performance of innovation ecosystems based on the performance of the innovation ecosystems of 64 countries assessed by the Global Innovation Index 2022. The methodology consists of multiple hierarchical linear regressions, in which the impact factors on innovation ecosystems, measured through indicators, are the independent variables and innovation performance, in knowledge and technology and in creativity, are the dependent variables in an iterative process, using STATA/MP 18.0 data analysis software. The results indicate that human capital and research (the basis of business and innovative products aimed at filling gaps in the market are people with a good higher education, which is also linked to local university rankings) and business sophistication (highly qualified work, leveraging strategic partnerships, and with knowledge absorption capacity) are the main pillars determining innovation performance at a global level. Education (an educated workforce is of growing importance in the knowledge era), R&D investment (including support from the state in the form of tax incentives for whoever invests in R&D), innovation partnerships (for a faster, more open innovation effort), ecological sustainability (a new reinforced priority after COVID-19) and knowledge absorption (to absorb one must first detain valuable knowledge in the area) are the variables with the greatest impact on innovation performance. The work provides guidance on which areas should be prioritized in the development of policies and strategies to accelerate innovation in countries. The study is limited by the time frame and reveals, by comparison with pre-pandemic studies, that the determinants of innovation can be dynamic, varying according to the countries and, consequently, the global context of the analysis.