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Malayan pangolin SARS-CoV-2-related coronavirus (SARSr-CoV-2) is closely related to SARS-CoV-2. However, little is known about its pathogenicity in pangolins. Using CT scans we show that SARSr-CoV-2 positive Malayan pangolins are characterized by bilateral ground-glass opacities in lungs in a similar manner to COVID-19 patients. Histological examination and blood gas tests are indicative of dyspnea. SARSr-CoV-2 infected multiple organs in pangolins, with the lungs the major target, and histological expression data revealed that ACE2 and TMPRSS2 were co-expressed with viral RNA. Transcriptome analysis indicated that virus-positive pangolins were likely to have inadequate interferon responses, with relative greater cytokine and chemokine activity in the lung and spleen. Notably, both viral RNA and viral proteins were detected in three pangolin fetuses, providing initial evidence for vertical virus transmission. In sum, our study outlines the biological framework of SARSr-CoV-2 in pangolins, revealing striking similarities to COVID-19 in humans. Author summary: SARS-CoV-2 has caused a severe and ongoing global pandemic. To date, bats and pangolins are the only groups of mammals known carry SARS-CoV-2-related coronaviruses (SARSr-CoV-2). Although the SARSr-CoV-2 detected in confiscated Malayan pangolins from Guangdong, China (PCoV-GD) has lower sequence similarity to SARS-CoV-2 than some bat-derived viruses, its receptor-binding domain within the S protein that binds to host ACE2 receptors for entry into cells is almost identical to that of SARS-CoV-2. Here, we determined the pathogenicity, tissue tropism and transcriptional response of PCoV-GD in deceased adult Malayan pangolins and their fetuses. Notably, virus-positive pangolins showed ground-glass opacities in their lungs similar to COVID-19 pneumonia and blood gas tests that were indicative of dyspnea. We detected viral RNA in multiple pangolin tissues, including liver, intestine, heart, kidney, spleen and skeletal muscle. This is similar to autopsy reports in COVID-19 patients and is associated with multiple organ dysfunction syndrome. The virus-positive pangolins showed an inadequate interferon response. In addition, PCoV-GD was detected in pangolin fetuses, suggesting the potential vertical transmission of the virus in utero. In sum, Malayan pangolins infected with a PCoV-GD display a pathology that is strikingly similar to human COVID-19. [ABSTRACT FROM AUTHOR]