Introduction Clinically, the early prediction of the severity of COVID-19 is often challenging, as a dramatic change in severity can occur without warning. The severity of COVID-19 disease is associated with an increased level of inflammatory mediators, including cytokines. This study aimed to evaluate the association of the levels of cytokines interleukin (IL)-2, IL-6, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and IL-10 with the severity of COVID-19 in Bangladesh. Materials and methods This cross-sectional study included a total of 60 confirmed cases of COVID-19, comprising 30 severe cases (Group A) and 30 non-severe cases (Group B), and 10 healthy individuals (Group C) attending Bangabandhu Sheikh Mujib Medical University (BSMMU) from March 2021 to February 2022. The cytokine assay was performed using the human Th1/Th2/Th17 cytokine kit BD cytometric bead array (CBA) on the BD Accuri C6 Plus flow cytometer. Statistical analysis was conducted using IBM SPSS Statistics for Windows, Version 23 (Released 2015; IBM Corp., Armonk, New York). Results The mean ages of the patients in Groups A, B, and C were 60.73±5.97, 57.13±7.68, and 48.10±9.13 years, respectively, with a male predominance in all groups. The mean IL-2, IL-6, IL-10, and TNF-α levels had a positive correlation with the increased age group and male gender, although it was not statistically significant. The mean IL-6 and IFN-γ levels were significantly higher among severe cases (216.95±147.78 and 0.98±0.95 pg/mL, respectively) compared to non-severe cases (94.29±128.79 and 0.41±0.61 pg/mL, respectively) and healthy individuals (1.08±1.97 and 0.15±0.28 pg/mL, respectively). Furthermore, the anti-inflammatory cytokine IL-10 was also significantly higher among severe cases (17.92±21.87 pg/mL) compared to non-severe cases (5.38±6.73 pg/mL) and healthy individuals (1.62±1.65 pg/mL). Conclusion IL-6, IFN-γ, and IL-10 have a significant association with the severity of COVID-19 disease. Clinicians treating patients with COVID-19 can consider the level of these cytokines as biomarkers of severity.