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Dysregulated immune cell responses have been linked to the severity of Coronavirus Disease 2019 (COVID-19). However, the specific viral factor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contributing to the immune-dysregulation is currently unclear. Herein, we identified the ectodomain of Ig-like fold viral proteinSARS-CoV-2 Orf7a interacted with CD14+ monocytes at the highest efficiency in human peripheral blood mononuclear cells, but not for the relative highly pathogenic protein SARS-CoV Orf7a. The 2.2 A resolutioncrystal structure of SARS-CoV-2 Orf7a reveals three remarkable changes in the amphipathic side of the four-strand β-sheet, implying the potential functional interface of the viral protein. Structure-based superimposition of SARS-CoV-2 Orf7a with SARS-CoV Orf7a - LFA1 working model suggests that SARS-CoV-2 Orf7a utilizes different binding patterns to recognize the specific immune cells. Importantly, SARS-CoV-2 Orf7a co-incubation with CD14+ monocytes ex vivo triggers a decrease of HLA-DR/DP/DQ and significant pro-inflammatory cytokines expressions, including IL-6, IL-1β, IL-8, and TNF-α. Our work demonstrates that SARS-CoV-2 Orf7a is an immunomodulating factor for immune cells binding and trigging aberrant inflammatory responses, providing promising therapeutic drug targets in the pandemic disease COVID-19. Funding: This work is supported by the National Key RD the Special Fund for Scientific and Technological Innovation Strategy of Guangdong Province of China (2018B030306029), COVID-19 Emerging Prevention Products, Research Special Fund of Zhuhai City (ZH22036302200016PWC) granted to S.C.; the Fundamental Research Funds for the Central Universities (19ykzd36) granted to J.C; and the Science and Technology Program of Guangzhou (202002030069) granted to J.C. Conflict of Interest: The authors declare no conflict of interest. Ethical Approval: The human peripheral blood samples for the experiments were collected through The Health Management Center, The Fifth Affiliated Hospital, Sun Yat-sen University. This study was approved by The Medical Ethics Committee of The Fifth Affiliated Hospital, Sun Yat-sen University (2020-K195-1).