Hematological problems are associated with Coronavirus disease 2019 (COVID-19). Respiratory impairment is the higher point studied, although without experimental studies related to the oxygen transport performed by erythrocytes. Therefore, we decided to investigate if erythrocytes from COVID-19 patients have their functionality changed. The case-control study included hospitalized patients with a positive real-time polymerase chain reaction (RT-PCR) result admitted to University Hospital. Volunteers (negative RT-PCR results) were recruited as a control group. Thus, we assessed different erythrocytes parameters, oxidative stress markers, and biophysical studies using whole blood and isolated hemoglobin. We found a decrease of 51% in oxygen uptake and reduced antioxidant enzyme activity in COVID-19 patients compared to controls. Raman spectrometry showed structural changes in the hemoglobin and lipids of the erythrocytes from COVID-19 patients; thus, these results were consolidated with an increase in Young’s modulus in erythrocytes followed by morphology changes. Besides, isolated hemoglobin from COVID-19 patients has a distinct interaction profile using a ligand model compared to the control. COVID-19 leads to structural, functional, and morphological damage to human erythrocytes. Our data showed structural and molecular changes and induction of oxidative stress in erythrocytes by COVID-19, a new perspective on the contribution of erythrocytes to a respiratory commitment in COVID-19.