Streptococcus pyogenes (Group A Streptococcus; GAS) is a high-priority for vaccine development as recognised by the World Health Organisation. Despite decades of concerted effort, vaccine-related research has historically been hindered by a lack of suitable models. The human infection model with emm75 GAS (Controlled Human Infection for Vaccination Against Streptococcus; CHIVAS) provides a remarkable opportunity to better understand critical host-pathogen dynamics pertaining to disease progression and prevention. From the CHIVAS trial, we collected saliva before, during, and after controlled pharyngitis in 20 healthy adult participants and analysed the salivary proteome. Our in-depth analysis using data-independent acquisition (DIA) mass spectrometry revealed a striking increase of plasma proteins in the oropharynx during acute illness, with the most dramatic changes occurring at 48-hours post-challenge, accompanied by a decrease of salivary proteins. Elevated proteins included key players of general inflammation, innate immunity, and the acute phase response. Moreover, human proteins known to be exploited by key GAS virulence mechanisms were increased locally during peak illness at the site of infection. We have, for the first time, robustly characterised the local host response to acute pharyngitis in humans, advancing us towards a holistic elucidation of the pathogenesis of GAS.