Abstract Background The COVID-19 pandemic has highlighted the need for equitable and timely access to vaccination. Limited evidence is available on how to implement vaccination campaigns (VCs) that are sustainable and responsive to changes in real-world health policy and practice contexts. We present lessons learned from the implementation of a COVID-19 VC in the Boeny region of Madagascar. Methods Informed by the Dynamic Sustainability Framework, VC implementation was continuously reviewed during multisectoral stakeholder feedback rounds, key informant interviews, and problem-solving meetings to identify and put key adaptations throughout the campaign process into practice. Outcome indicators include pre- and post-VC vaccine hesitancy and trends in vaccine doses deployed were analyzed using generalized linear models. Results Key adaptations of the implementation strategy included community-led awareness-raising and outreach activities also in remote areas, strengthening VC through the training of 340 staff, and addressing gaps identified in the cold chain, waste management, vaccine transportation, and IT equipment. Overall, 24888 COVID-19 vaccines were administered in six months. Changes in campaign strategy increased the number of doses administered by 8% (RR = 1.08; CI 95%: 1.01; 1.15) per week. No changes in vaccine hesitancy post-VC were observed in an unvaccinated population(Δ = 0.02, CI 95%: -0.04; 0.08). Conclusions Collaborative and dynamic multi-sectoral VC strategies that combine healthcare-based approaches with pro-active outreach and community-led awareness-raising activities are essential in increasing vaccine uptake in limited-resource settings. Our findings show that despite boosting vaccination coverage, such initiatives may not have an impact on COVID-19 vaccine hesitancy at the community level Key messages • Multisectoral stakeholder collaboration and engagement are key to successful vaccination campaign implementation. • A Dynamic Sustainability Framework approach can be effective in ensuring a continuous fit between campaign and its setting.