The study aimed to map the geographic extent and severity of artemisinin resistance in *Plasmodium falciparum* malaria across mainland Southeast Asia. Between May 2011 and April 2013, 1241 adults and children with acute, uncomplicated falciparum malaria were enrolled in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate for 3 days followed by a standard 3-day course of artemisinin-based combination therapy. The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand–Cambodia border. Slowly clearing infections (half-life >5 hours) were associated with single point mutations in the "propeller" region of the *P. falciparum* kelch protein gene (*kelch13*). These mutations were detected throughout mainland Southeast Asia, from southern Vietnam to central Myanmar. In western Cambodia, where artemisinin-based combination therapies are failing, a 6-day course of antimalarial therapy was associated with a cure rate of 97.7% at 42 days. Artemisinin resistance, characterized by slow parasite clearance, is now prevalent across mainland Southeast Asia and is associated with mutations in *kelch13*. Prolonged courses of artemisinin-based combination therapies remain efficacious in areas where standard 3-day treatments are failing.The study aimed to map the geographic extent and severity of artemisinin resistance in *Plasmodium falciparum* malaria across mainland Southeast Asia. Between May 2011 and April 2013, 1241 adults and children with acute, uncomplicated falciparum malaria were enrolled in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate for 3 days followed by a standard 3-day course of artemisinin-based combination therapy. The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand–Cambodia border. Slowly clearing infections (half-life >5 hours) were associated with single point mutations in the "propeller" region of the *P. falciparum* kelch protein gene (*kelch13*). These mutations were detected throughout mainland Southeast Asia, from southern Vietnam to central Myanmar. In western Cambodia, where artemisinin-based combination therapies are failing, a 6-day course of antimalarial therapy was associated with a cure rate of 97.7% at 42 days. Artemisinin resistance, characterized by slow parasite clearance, is now prevalent across mainland Southeast Asia and is associated with mutations in *kelch13*. Prolonged courses of artemisinin-based combination therapies remain efficacious in areas where standard 3-day treatments are failing.