The lymphopenia as a major immunological abnormality occurs in the majority of severe COVID‐19 patients, which is strongly associated with mortality rate. A low proportion of lymphocytes may express the main receptor for SARS‐CoV‐2, called angiotensin‐converting enzyme 2 (ACE2). Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) can also use ACE2‐independent pathways to enter lymphocytes. Both SARS‐CoV‐2‐ and immune‐mediated mechanisms may contribute to the occurrence of lymphopenia through influencing the lymphocyte production, survival or tissue re‐distribution. The metabolic and biochemical changes can also affect the production and survival of lymphocytes in COVID‐19 patients. Lymphopenia can cause general immunosuppression and promote cytokine storm, both of them play an important role in the viral persistence, viral replication, multi‐organ failure and eventually death. Here, a comprehensive view concerning the possible mechanisms that may lead to the lymphocyte reduction in COVID‐19 patients is provided, while highlighting the potential intervention approaches to prevent lymphopenia.

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