Zoonotic pathogens such as SARS-CoV-2 and Influenza viruses pose significant global health challenges due to their ability to cross species barriers and cause widespread disease in humans. Attachment and entry are an essential bottleneck for zoonotic viruses and decide over a successful infection of a novel host organism. At this stage host entry factors could favor viral uptake while host restriction factors could prevent the initial steps of virus infection. Profiling host entry factors can aid in the development of broad-spectrum antivirals that are effective against multiple viruses sharing similar entry pathways, enhancing our preparedness against a range of viral threats. Our comprehension of host restriction factors, that form the frontline of innate defense against viral infections continues to evolve. Host restriction factors are promising diagnostic markers for viral infections and their activity can be modulated to enhance the host’s ability to control infection. In this work, we applied cell surface proximity ligation assay (CSPL) coupled to mass spectrometry (LC-ESI MSMS) analysis to identify host entry and restriction factors of Influenza A (IAV) and SARS-CoV-2 viruses. A functional involvement of the identified proteins in virus entry was confirmed by genetic loss and gain of function approaches. Among the obtained candidates, transferrin receptor (TfR1) and solute carrier family 3 membrane 2 (SLC3A2) proteins were shown to be required for the entry of IAV and SARS-CoV-2 viruses, respectively. In line with this, chemical inhibition of TfR1 (in vitro and in vivo) and SLC3A2 (in vitro) using small molecule compounds confirmed the previously observed phenotypes and suggested druggability of the two targets. Surprisingly, a headless TfR1 mutant still facilitated the uptake of IAV, which was lost in the presence of recycling-deficient TfR1 mutants thereby indicating the importance of the TfR1 recycling mechanism for IAV entry without the requirement for direct binding. The mechanism by which SLC3A2 enhances SARS-CoV-2 virus entry still needs to be elucidated. On the other side through CSPL analysis, we have identified host restriction factors such as lymphocyte antigen 75 (LY75) and prominin 1 (PROM1) that inhibit SARS CoV-2 infection and replication in Calu3 lung epithelial cells. Mechanistically, both factors reduce the proteolytic processing of the spike protein, potentially explaining the decreased SARS-CoV-2 infection. PROM1, in particular, interferes with the catalytic activity of furin, potentially through direct 3 binding, which in turn inhibits spike protein processing and renders virions non-infectious. However the mechanism behind LY75s reduction in spike protein processing remains unclear. Our work has uncovered host entry factors for IAV and SARS-CoV-2 viruses, providing potential therapeutic targets. Additionally, we've identified host restriction factors that play crucial roles in early barriers against SARS-CoV-2 infection. Utilizing the CSPL technique, we can systematically identify both entry and restriction factors across a spectrum of viruses, presenting a novel approach to understanding viral pathogenesis.