In immediate responses to the COVID-19 crisis, science and innovation are playing essential roles in providing a better scientific understanding of the virus, as well as in the development of vaccines, treatments and diagnostics. Both the public and private sectors have poured billions of dollars into these efforts, accompanied by unprecedented levels of global cooperation. However, the economic crisis that is currently unfolding is expected to severely curtail research and innovation expenditures in firms, while debt-laden governments will face multiple, competing demands for financial support. These developments threaten to cause long-term damage to innovation systems at a time when science and innovation are most needed to deal with the climate emergency, meet the Sustainable Development Goals, and accelerate the digital transformation. Governments will need to take measures to protect their innovation systems as part of their stimulus and recovery packages, but should also use these as opportunities for reforms. In particular, science, technology and innovation (STI) policy should shift towards supporting a more ambitious agenda of system transformation that promotes a managed transition to more sustainable, equitable and resilient futures.