The emergence of COVID-19 in March 2020 challenged Zimbabwe to respond with limited medical facilities and therapeutic options. Based on early clinical indications of efficacy for the macrocyclic lactone, Ivermectin (IVM), against COVID-19, IVM-based combination treatments were deployed to treat it. Oxygen saturation (SpO2) data were retrospectively analyzed for 34 severe, hypoxic COVID-19 patients all on room air (without supplemental oxygen). The patients, median age 56.5, were treated at clinics or at home between August 2020 and May 2021. All but three of these 34 patients had significantly increased SpO2 values within 24 h after the first IVM dose. The mean increase in SpO2 as a percentage of full normalization to SpO2 = 97 was 55.1% at +12 h and 62.3% at +24 h after the first IVM dose (paired t-test, p < 0.0000001). These results parallel similar sharp, rapid increases in SpO2, all on room air, for 24 mostly severe COVID-19 patients in the USA (California) who were given an IVM-based combination treatment. All patients in both of these critical series recovered. These rapid increases in SpO2 values after IVM treatment stand in sharp contrast to declines in SpO2 and associated pulmonary function through the second week following the onset of moderate or severe COVID-19 symptoms under standard care.