Streptococcus pyogenes (Group A Streptococcus; Strep A) is a significant human pathogen responsible for a diverse range of tissue infections. As a leading cause of infectious disease-related mortality, Strep A is recognised by the World Health Organisation as a high-priority for vaccine development. The human infection model with emm75 Strep A (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 clinical trial, we collected saliva before, during, and after controlled pharyngitis in 20 healthy adult participants and analysed the salivary proteome boxcar data-independent acquisition (DIA) mass spectrometry. We detected 1244 proteins in total, with 720 reliably detected across all 20 participants. We observed 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, such as fibrinogen, increased locally during peak illness. 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.