The large-scale dissemination of coronavirus disease-2019 (COVID-19) and its serious complications have pledged the scientific research communities to uncover the pathogenesis mechanisms of its etiologic agent, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Methods of unveiling such mechanisms are rooted in understanding the viral agent's interactions with the immune system, including its ability to activate macrophages, due to their suggested role in prolonged inflammatory phases and adverse immune responses. The objective of this study is to test the effect of SARS-CoV-2-free proteins on the metabolic and immune responses of macrophages. We hypothesized that SARS-CoV-2 proteins shed during the infection cycle may dynamically induce metabolic and immunologic alterations with an inflammatory impact on the infected host cells. It is imperative to delineate such alterations in the context of macrophages to gain insight into the pathogenesis of these highly infectious viruses and their associated complications and thus, expedite the vaccine and drug therapy advent in combat of viral infections. Human monocyte-derived macrophages were treated with SARS-CoV-2-free proteins at different concentrations. The phenotypic and metabolic alterations in macrophages were investigated and the subsequent metabolic pathways were analyzed. The obtained results indicated that SARS-CoV-2-free proteins induced concentration-dependent alterations in the metabolic and phenotypic profiles of macrophages. Several metabolic pathways were enriched following treatment, including vitamin K, propanoate, and the Warburg effect. These results indicate significant adverse effects driven by residual viral proteins that may hence be considered determinants of viral pathogenesis. These findings provide important insight as to the impact of SARS-CoV-2-free residual proteins on the host cells and suggest a potential new method of management during the infection and prior to vaccination.