Despite mounting evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engagement with immune cells, most express little, if any, of the canonical receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2). Here, using a myeloid cell receptor-focused ectopic expression screen, we identified several C-type lectins (DC-SIGN, L-SIGN, LSECtin, ASGR1, and CLEC10A) and Tweety family member 2 (TTYH2) as glycan-dependent binding partners of the SARS-CoV-2 spike. Except for TTYH2, these molecules primarily interacted with spike via regions outside of the receptor-binding domain. Single-cell RNA sequencing analysis of pulmonary cells from individuals with coronavirus disease 2019 (COVID-19) indicated predominant expression of these molecules on myeloid cells. Although these receptors do not support active replication of SARS-CoV-2, their engagement with the virus induced robust proinflammatory responses in myeloid cells that correlated with COVID-19 severity. We also generated a bispecific anti-spike nanobody that not only blocked ACE2-mediated infection but also the myeloid receptor-mediated proinflammatory responses. Our findings suggest that SARS-CoV-2-myeloid receptor interactions promote immune hyperactivation, which represents potential targets for COVID-19 therapy. Display omitted •C-type lectins and TTYH2 are myeloid cell-interacting partners of SARS-CoV-2 spike•C-type lectins interact with spike largely through regions outside of the RBD•Myeloid receptors promote SARS-CoV-2 proinflammatory responses but not infection•A bispecific nanobody blocked SARS-CoV-2 infection and inflammatory responses Most immune cells express little, if any, of the canonical SARS-CoV-2 receptor, ACE2. Lu et al. report that C-type lectins and TTYH2 act as SARS-CoV-2 myeloid cell-interacting partners that trigger immune hyperactivation but not infection. These findings raise the possibility that these virus-myeloid cell interactions are directly involved in COVID-19 immunopathogenesis and could be targeted for COVID-19 therapy.