The pandemic COVID19 illness caused by SARS-CoV-2, which produces pneumonia and lower respiratory tract infections, is a serious public health concern, with frightening mutations causing over 4.5 million deaths globally. Whilst effective immunisation showed promise globally, several antiviral treatments are being clinically evaluated to fill the “therapeutic gap” in treating infected people. Understanding the entire repertoire of diverse host factors engaged by SARS-CoV-2 for entry and pathogenicity is required for long-lasting potential therapeutics or vaccines. Here, using a structural and molecular approach, we show multistage processing of SARS-CoV-2 spike-protein for virion activation, infection, and how mutations influence it. We solved the structures of spike-protein in complex with different host cell factors (TMPRSS2, Furin, CD26 (DPP4), and NRP1) with computational and molecular dynamics. The structural studies insights into the process of how viral spike-protein engages with these multiple host factors, in addition to ACE2, to hijack host cell entry. Furthermore, screening host genetics and sequencing reveal alleles V160M in TMPRSS2 and mutation in Furin provided protection from COVID19. Besides, our large-scale retrospective cohort studies proved Arbidol and derivatives as a potential therapy for COVID19, and we structurally established the mechanism of action in disrupting spike function. These findings cognize our understanding complexity of the SARS-CoV-2 spike-protein making varied entry routes and reveal the broad mechanism of viral spike glycoprotein cascading into the host cell, paving the door for future vaccine development and identifying key targets.