COVID-19 is a world disaster. In response to COVID-19 quarantine, stress, anxiety, and depression may easily develop which negatively affect immunity and decrease the patient’s response against the COVID-19 virus. This study investigated the effect of an integrated intervention combining cognitive-behavioural stress management (CBSM) and progressive muscle relaxation (PMRs) on immune biomarkers and disease severity and progression in patients with COVID-19 and the period to which these changes last. Thirty patients with mild or moderate COVID-19 were randomly distributed into intervention and control groups. The intervention group performed an integrated intervention combining CBSM and PMRs. There were three outcome measures including blood immune markers, salivary immunoglobulin A, and Wisconsin scale (WIS). Two-week post-intervention, there were significant differences between groups in the WIS total score, Leucocytes, Lymphocytes, Interleukin-6, and Immunoglobulin-A. While there were non-significant differences between both groups in Interleukin-10 and TNF-α. The significant differences between groups in the WIS total score, Leucocytes, Lymphocytes, Interleukin-6, and Immunoglobulin-A significantly continued 1 week as a follow-up. This study concluded that performing an integrated intervention combining CBSM and PMRs for 2 weeks significantly increases immune biomarkers mainly Leucocytes, Lymphocytes, Interleukin-10, and Interleukin-6 along with S-IgA. Also, this protocol significantly decreases disease severity and associated stress, anxiety, and depression; and enhances the quality of life in patients with COVID-19. The study was retrospectively registered with NCT04998708.