The COVID-19 pandemic triggered unprecedented scientific efforts worldwide and launched several initiatives to promote international cooperation. Because international scientific collaborations between high-income countries (HICs) and low- and middle-income countries (LMICs) are not always balanced, analyzing research leadership helps to understand the global dynamics of knowledge production during COVID-19. In this study, we focused on HIC–LMIC collaborations on COVID-19 research in 469,937 scientific publications during the first 2 years of the pandemic (2020–2021). Co-authorship and authors’ affiliation were used to identify international collaborations, according to country income level. The leadership analysis considered the countries of the first and last authors of publications. The results show that (i) most publications with international collaborations (49.3%) involved researchers from HICs and LMICs; (ii) collaborative research between HICs and LMICs addressed relevant public health needs; (iii) HIC–LMIC collaborations were primarily led by researchers from the United States, China, the United Kingdom, and India; (iv) most HIC–LMIC publications (44%) had shared leadership, with research interests linked to national expertise and global interests. This study contributes to the analysis of research collaborations on COVID-19 and sheds light on North–South relations in the production and dissemination of scientific knowledge.