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Concerns that infection with SARS-CoV-2, the etiological agent of COVID-19, may cause new-onset diabetes persist amidst an evolving research landscape, and precise risk assessment is hampered by at times conflicting evidence. Here, leveraging comprehensive single-cell analyses of in vitro SARS-CoV-2-infected human pancreatic islets, we demonstrate that productive infection is strictly dependent on the SARS-CoV-2 entry receptor ACE2 and targets all pancreatic cell types. Importantly, the infection remains highly circumscribed, largely non-cytopathic, and despite high viral burden in infected subsets, promotes only modest cellular perturbations and inflammatory responses. Similar experimental outcomes are also observed after islet infection with endemic coronaviruses. Thus, the limits of pancreatic SARS-CoV-2 infection, even under in vitro conditions of enhanced virus exposure, do not support the proposition that in vivo targeting of beta cells by SARS-CoV-2 precipitates new-onset diabetes. If restricted pancreatic damage accrued by COVID-19 increases cumulative diabetes risk, however, remains to be evaluated. Funding: These efforts were supported by JDRF 3-PDF-2018-575-A-N (V.v.d.H.); NIH/NIDDK R01DK12392, NIH/NIAID P01AI042288 and NIH/NIAID U54AI142766-S1 (M.A.A.); NIH/NIAID Center of Excellence for Influenza Research and Response/Center for Research for Influenza Pathogenesis and Transmission contract # 75N93019R00028, NIH/NIAID U19AI135972 (supplement), Defense Advanced Research Projects Agency HR0011-19-2-0020, JPB Foundation, and Open Philanthropy Project # 2020-215611 (5384), Anonymous (A.G.-S.); NIH/NIAID R01AI151029 and NIA/NIAID U01AI150748 (B.R.R.); NIH/NIDDK R01DK130425 (M.S.); and NIH/NIAID R01AI134971, NIH/NIDDK U01DK123716, NIH/NIDDK U01DK104162, NIH/NIDDK P30DK020541 and NIH/NIDDK R01DK130425 (D.H.). Funding: The AG-S laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines and Merck, outside of the reported work. Declaration of Interests: AG-S has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories and Pfizer, outside of the reported work. AG-S is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work. All other authors declare no conflict of interest. Ethics Approval Statement: Our study is considered “not human subjects research” since all donor islet preparations were provided as de-identified tissue specimens by a commercial purveyor