The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in a global pandemic, leading to the need for effective surveillance and monitoring strategies. The identification of SARS-CoV-2 peptides and acute phase response proteins in wastewater using mass spectrometry (MS) and the wastewater-based epidemiology concept is a promising tool for the surveillance of infectious diseases. MS provides high specificity and sensitivity for the identification of SARS-CoV-2 peptides in wastewater, allowing for early detection of outbreaks and real-time monitoring of disease trends. The quantification of acute phase response proteins in wastewater provides valuable information on the dynamics of the immune response to SARS-CoV-2, including the kinetics of cytokine production and the levels of acute phase response proteins in wastewater samples. In this study, we developed the first comprehensive mass spectrometry-based framework enabling simultanous tracking of infectious disease spread and community response to facilitate rapid disease management at the community level. SARS-CoV-2 was used as a test pathogen and C-reactive protein (CRP) as an acute phase response protein. The high specificity and sensitivity of MS, combined with the ability to provide a population-level perspective on the spread of the virus, make it a valuable tool for the surveillance of SARS-CoV-2. To our knowledge, this is the first report to use LCMS/MS to measure SARS-CoV-2 and its corresponding acute phase responsive human CRP protein in wastewater.