Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is subject to restriction by several interferon-inducible host proteins. To identify novel factors that limit replication of the virus, we tested a panel of genes that we found were induced by interferon treatment of primary human monocytes by RNA sequencing. Further analysis showed that one of the several candidates genes tested, receptor transporter protein 4 (RTP4), that had previously been shown to restrict flavivirus replication, prevented the replication of the human coronavirus HCoV-OC43. Human RTP4 blocked the replication of SARS-CoV-2 in susceptible ACE2.CHME3 cells and was active against SARS-CoV-2 Omicron variants. The protein prevented the synthesis of viral RNA, resulting in the absence of detectable viral protein synthesis. RTP4 bound the viral genomic RNA and the binding was dependent on the conserved zinc fingers in the amino-terminal domain. Expression of the protein was strongly induced in SARS-CoV-2-infected mice although the mouse homolog was inactive against the virus, suggesting that the protein is active against another virus that remains to be identified. IMPORTANCE The rapid spread of a pathogen of human coronavirus (HCoV) family member, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), around the world has led to a coronavirus disease 2019 (COVID-19) pandemic. The COVID-19 pandemic spread highlights the need for rapid identification of new broad-spectrum anti-coronavirus drugs and screening of antiviral host factors capable of inhibiting coronavirus infection. In the present work, we identify and characterize receptor transporter protein 4 (RTP4) as a host restriction factor that restricts coronavirus infection. We examined the antiviral role of hRTP4 toward the coronavirus family members including HCoV-OC43, SARS-CoV-2, Omicron BA.1, and BA.2. Molecular and biochemical analysis showed that hRTP4 binds to the viral RNA and targets the replication phase of viral infection and is associated with reduction of nucleocapsid protein. Significant higher levels of ISGs were observed in SARS-CoV-2 mouse model, suggesting the role of RTP4 in innate immune regulation in coronavirus infection. The identification of RTP4 reveals a potential target for therapy against coronavirus infection.