PurposeWe investigated the association of COVID-19 indicators and economic uncertainty indices on payment-based system cryptocurrency (i.e. Bitcoin, Ripple and Dogecoin) returns.Design/methodology/approachWe used an autoregressive distributed lag (ARDL) model for panel data and performed robustness checks by utilizing a random effect model (REM) and generalized method of moments (GMM). There are 25 most adopted cryptocurrency’s countries and the data spans from 22 March 2021 to 6 May 2022.FindingsThis research discovered four findings: (1) the index of COVID-19 vaccine confidence (VCI) recovers the economic and Bitcoin has become more attractive, causing investors to shift their investment from Dogecoin to Bitcoin. However, the VCI was revealed to be insignificant to Ripple; (2) during uncertain times, Bitcoin could perform as a diversifier, while Ripple could behave as a diversifier, safe haven or hedge. Meanwhile, the movement of Dogecoin prices tended to be influenced by public figures’ actions; (3) public opinion on Twitter and government policy changes regarding COVID-19 and economy had a crucial role in investment decision making; and (4) the COVID-19 variants revealed insignificant results to payment-based system cryptocurrency returns.Originality/valueThis study contributed to verifying the vaccine confidence index effect on payment-based system cryptocurrency returns. Also, we further investigated the uncertainty indicators impacting on cryptocurrency returns during the COVID-19 pandemic. Lastly, we utilized the COVID-19 variants as a cryptocurrency returns’ new determinant.