Background: Governance of coronavirus disease 2019 (COVID-19) responses has been challenging for all countries. Syria has been particularly challenged, due to protracted multi-party conflict and debilitated health systems fragmented across several governance areas. To improve response governance, we need a better understanding of frontline response policy implementation across the country. This study explored perspectives of COVID-19 response governance among frontline healthcare providers over time and across all areas of Syria. Methods: We used a qualitative longitudinal study design, conducting five rounds of remote semi-structured key informant interviews in Arabic (i.e., approximately 8 interviews each in March 2020, July 2020, September 2020, December 2020, and September 2021) with 14 purposively sampled public and private healthcare providers in the three main areas-of-control [i.e., opposition-controlled area (OCA), autonomous administration-controlled area (AACA), al-Assad government-controlled area (GCA)]. We conducted integrative thematic analysis in Arabic, within and across geography and time, as described by Neale [2021]. Results: Almost all participants across all areas and rounds expressed distrust of local health authorities and dissatisfaction with COVID-19 response governance. This was most apparent in initial rounds and in GCA. Response planning was identified as insufficient, non-participatory, and non-transparent, with limited infrastructure and resources as the main challenges across time. Anticipated rapid virus spread and health systems collapse did not occur. Community adherence to prevention measures varied, starting weakly due to public skepticism, increasing immediately after first cases were confirmed and then fluctuating with case numbers and challenges of insecurity and misinformation. Perceptions of COVID-19 vaccination were positive, while low uptake and hesitancy were attributed to misinformation, disinformation, and disinterest. Participant optimism increased over time. Suggested improvements to COVID-19 response governance focused on strengthening current health systems’ capacity and improving coordination. Conclusions: Addressing transparency and misinformation should be a first step to improving public engagement and trust and thus response governance for COVID-19 and future health emergencies.