BackgroundLittle is known about the role of the World Health Organization (WHO) in communicating with the public on social media during a global health emergency. More specifically, there is no study about the relationship between the agendas of the WHO and Twitter users during the COVID-19 pandemic.ObjectiveThis study utilizes the network agenda-setting model to investigate the mutual relationship between the agenda of the WHO’s official Twitter account and the agenda of 7.5 million of its Twitter followers regarding COVID-19.MethodsContent analysis was applied to 7090 tweets posted by the WHO on Twitter from January 1, 2020, to July 31, 2020, to identify the topics of tweets. The quadratic assignment procedure (QAP) was used to investigate the relationship between the WHO agenda network and the agenda network of the 6 Twitter user categories, including “health care professionals,” “academics,” “politicians,” “print and electronic media,” “legal professionals,” and the “private sector.” Additionally, 98 Granger causality statistical tests were performed to determine which topic in the WHO agenda had an effect on the corresponding topic in each Twitter user category and vice versa.ResultsContent analysis revealed 7 topics that reflect the WHO agenda related to the COVID-19 pandemic, including “prevention,” “solidarity,” “charity,” “teamwork,” “ill-effect,” “surveillance,” and “credibility.” Results of the QAP showed significant and strong correlations between the WHO agenda network and the agenda network of each Twitter user category. These results provide evidence that WHO had an overall effect on different types of Twitter users on the identified topics. For instance, the Granger causality tests indicated that the WHO tweets influenced politicians and print and electronic media about “surveillance.” The WHO tweets also influenced academics and the private sector about “credibility” and print and electronic media about “ill-effect.” Additionally, Twitter users affected some topics in the WHO. For instance, WHO followers affected “charity” and “prevention” in the WHO.ConclusionsThis paper extends theorizing on agenda setting by providing empirical evidence that agenda-setting effects vary by topic and types of Twitter users. Although prior studies showed that network agenda setting is a “one-way” model, the novel findings of this research confirm a “2-way” or “multiway” effect of agenda setting on social media due to the interactions between the content creators and audiences. The WHO can determine which topics should be promoted on social media during different phases of a pandemic and collaborate with other public health gatekeepers to collectively make them salient in the public.