Here, we report that the shedding proteases ADAM10 and ADAM17—independently of the protease TMPRSS2—facilitate two S protein‐dependent molecular events that contribute to COVID‐19 pathogenesis, SARS‐CoV‐2 infectivity, and SARS‐CoV‐2‐mediated lung cell fusion. Here, TMPRSS2 is linked to COVID-19.