Background: With a decline in malaria burden, innovative interventions and tools are required to reduce malaria transmission further. Mass drug administration (MDA) of artemisinin-based combination therapy (ACT) has been identified as a potential tool to further reduce malaria transmission, where coverage of vector control interventions is already high. However, the impact is limited in time. Combining an ACT with an endectocide treatment that is able to reduce vector survival, such as ivermectin (IVM), could increase the impact of MDA and offer a new tool to reduce malaria transmission. Objective: The study objective is to evaluate the impact of MDA with IVM plus dihydroartemisinin-piperaquine (DP) on malaria transmission in an area with high coverage of malaria control interventions. Methods: The study is a cluster randomized trial in the Upper River Region of The Gambia and included 32 villages (16 control and 16 intervention). A buffer zone of ~2 km was created around all intervention clusters. MDA with IVM plus DP was implemented in all intervention villages and the buffer zones; control villages received standard malaria interventions according to the Gambian National Malaria Control Program plans. Results: The MDA campaigns were carried out from August to October 2018 for the first year and from July to September 2019 for the second year. Statistical analysis will commence once the database is completed, cleaned, and locked. Conclusions: This is the first cluster randomized clinical trial of MDA with IVM plus DP. The results will provide evidence on the impact of MDA with IVM plus DP on malaria transmission.