During the latest pandemic, the RECOVERY study showed the benefits of dexamethasone (DEX) use in COVID‐19 patients. Obesity has been proven to be an independent risk factor for severe forms of infection, but little information is available in the literature regarding DEX dose adjustment according to body weight. We conducted a prospective, observational, exploratory study at Geneva University Hospitals to assess the impact of weight on DEX pharmacokinetics (PK) in normal‐weight versus obese COVID‐19 hospitalized patients. Two groups of patients were enrolled: normal‐weight and obese (body mass index [BMI] 18.5–25 and >30 kg/m², respectively). All patients received the standard of care therapy of 6 mg DEX orally. Blood samples were collected, and DEX concentrations were measured. The mean DEX AUC_0–8 and C_max were lower in the obese compared to the normal‐weight group (572.02 ± 258.96 vs. 926.92 ± 552.12 ng h/ml and 138.67 ± 68.03 vs. 203.44 ± 126.30 ng/ml, respectively). A decrease in DEX AUC_0–8 of 4% per additional BMI unit was observed, defining a significant relationship between weight and DEX AUC_0–8 (p = 0.004, 95% CI 2–7%). In women, irrespective of the BMI, DEX AUC_0–8 increased by 214% in comparison to men (p < 0.001, 95% CI 154–298%). Similarly, the mean C_max increased by 205% in women (p < 0.001, 95% CI 141–297%). Conversely, no significant difference between the obese and normal‐weight groups was observed for exploratory treatment outcomes, such as the length of hospitalization. BMI, weight, and gender significantly affected DEX AUC. We conclude that dose adjustment would be needed if the aim is to achieve the same exposures in normal‐weight and obese patients.