The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic causes a major health burden. Garlic organosulfur compounds, such as the diallyl thiosulfinate allicin exert strong antimicrobial activity against various respiratory pathogens. Here, we investigated the antiviral activity of allicin against SARS-CoV-2 in infected Vero E6 and Calu-3 lung cells. Allicin efficiently inhibited viral replication and infectivity in both cell lines. Proteome analyses of infected Calu-3 cells revealed a strong induction of the antiviral interferon-stimulated gene (ISG) signature (e.g. Mx1, IFIT, 2’5’OAS and ISG15), pathways of vesicular transport, tight junctions (KIF5A/B/C, OSBPL2, CLTC1, ARHGAP17) and ubiquitin modification (UBE2L3/5), as well as reprogramming of host metabolism, transcription and translation. Allicin abrogated the ISG host response and reverted the host cellular pathways to Mock levels, confirming the antiviral and immunomodulatory activity of allicin in the host proteome. Thus, biocompatible doses of garlic could be promising for protection of lung cells against SARS-CoV-2.