Selenium (Se) and zinc (Zn) are essential trace elements needed for appropriate immune system responses, cell signalling and anti-viral defence. A cross-sectional observational study was conducted at two hospitals in Ghent, Belgium, to investigate whether Se and/or Zn deficiency upon hospital admission correlates to disease severity and mortality risk in COVID-19 patients with or without comorbidities. Trace element concentrations along with additional biomarkers were determined in serum or plasma and associated to disease severity and outcome. An insufficient Se and/or Zn status upon hospital admission was associated with a higher mortality rate and a more severe disease course in the entire study group, especially in the senior population. In comparison to healthy European adults, the patients displayed strongly depressed total Se (mean ± SD: 59.2 ± 20.6 vs. 84.4 ± 23.4 μg L−1) and SELENOP (mean ± SD: 2.2 ± 1.9 vs. 4.3 ± 1.0 mg L−1) concentrations at hospital admission. Particularly strong associations were observed for death risk of cancer, diabetes and chronic cardiac disease patients with low Se status, and of diabetes and obese patients with Zn deficiency. A composite biomarker based on serum or plasma Se, SELENOP and Zn at hospital admission proved to be a reliable tool to predict severe COVID-19 course and death, or mild disease course. We conclude that trace element assessment at hospital admission may contribute to a better stratification of patients with COVID-19 and other similar infectious diseases, support clinical care, therapeutic interventions and adjuvant supplementation needs, and may prove of particular relevance for patients with relevant comorbidities.