Over the past two decades, anti-vaccine activism in the USA has evolved from a fringe subculture into an increasingly well organised, networked movement with important repercussions for public health. The COVID-19 pandemic has exacerbated this evolution and magnified the reach of vaccine misinformation. Anti-vaccine activists, who for many years spoke primarily to niche communities hesitant about childhood vaccinations, have used traditional and social media to amplify vaccine-related mistruths about COVID-19 vaccines while also targeting historically marginalised racial and ethnic communities. These efforts contributed to COVID-19 vaccine hesitancy and expanded the movement, with early indications suggesting that this hesitancy could now also be increasing hesitancy that existed pre-pandemic towards other vaccines. It is important to understand the implications of this recent evolution of anti-vaccine activism on vaccination uptake and the promotion of sound public health strategies. In this Viewpoint, we summarise the latest developments in US-based anti-vaccine activism and propose strategies for confronting them.