COVID-19 has resulted in over 645 million hospitalization and 7 million deaths globally. However, many questions still remain about clinical complications in COVID-19 and if these complications changed with different circulating SARS-CoV-2 strains. We analyzed a 2.5-year retrospective cohort of 47,063 encounters for 21,312 acute care patients at five Central Texas hospitals and define distinct trajectory groups (TGs) with latent class mixed modeling, based on the World Health Organization COVID-19 Ordinal Scale. Using this TG framework, we evaluated the association of demographics, diagnoses, vitals, labs, imaging, consultations, and medications with COVID-19 severity and broad clinical outcomes. Patients within 6 distinct TGs differed in manifestations of multi-organ disease and multiple clinical factors. The proportion of mild patients increased over time, particularly during Omicron waves. Age separated mild and fatal patients, though did not distinguish patients with severe versus critical disease. Male and Hispanic/Latino demographics were associated with more severe/critical TGs. More severe patients had a higher rate of neuropsychiatric diagnoses, consultations, and brain imaging, which did not change significantly in severe patients across SARS-CoV-2 variant waves. More severely affected patients also demonstrated an immunological signature of high neutrophils and immature granulocytes, and low lymphocytes and monocytes. Interestingly, low albumin was one of the best lab predictors of COVID-19 severity in association with higher malnutrition in severe/critical patients, raising concern of nutritional insufficiency influencing COVID-19 outcomes. Despite this, only a small fraction of severe/critical patients had nutritional labs checked (pre-albumin, thiamine, Vitamin D, B vitamins) or received targeted interventions to address nutritional deficiencies such as vitamin replacement. Our findings underscore the significant link between COVID-19 severity, neuropsychiatric complications, and nutritional insufficiency as key risk factors of COVID-19 outcomes and raise the question of the need for more widespread early assessment of patients' neurological, psychiatric, and nutritional status in acute care settings to help identify those at risk of severe disease outcomes.