While studies have elucidated many pathophysiological elements of COVID-19, little is known about immunological changes during COVID-19 resolution. We analyzed immune cells and phosphorylated signaling states at single-cell resolution from longitudinal blood samples of patients hospitalized with COVID-19, pneumonia and/or sepsis, and healthy individuals by mass cytometry. COVID-19 patients showed distinct immune compositions and an early, coordinated, and elevated immune cell signaling profile associated with early hospital discharge. Intra-patient longitudinal analysis revealed changes in myeloid and T cell frequencies and a reduction in immune cell signaling across cell types that accompanied disease resolution and discharge. These changes, together with increases in regulatory T cells and reduced signaling in basophils, also accompanied recovery from respiratory failure and were associated with better outcomes at time of admission. Therefore, although patients have heterogeneous immunological baselines and highly variable disease courses, a core immunological trajectory exists that defines recovery from severe SARS-CoV-2 infection. Patients were admitted to the hospital and enrolled in the study at day 0. Peripheral blood samples were collected up until day 28 of hospitalization. Corresponding clinical parameters and WHO scores were documented. 205 samples from 81 COVID-19-positive patients were included in the final cohort. Additionally, 14 samples from 7 COVID-19-negative patients with other respiratory diseases and 11 healthy individuals were included in the study. On average, we obtained 2 (range of 1–7) usable blood samples per patient. FCS files are normalized to remove batch effect and subsequently gated for CD45+ cells. File names represent 'batch_patientID day'.