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Background Due to their immediate exhalation after generation at the cellular/microbiome levels, exhaled volatile organic compounds (VOCs) may provide real-time information on pathophysiological mechanisms and host response to infections. In recent years, metabolic profiling of most frequent respiratory infection gained interest as it holds potential for early non-invasive detection of pathogens and monitoring of disease progression and response to therapy. Methods In contrast to previous studies with pre-selected patient groups, we conducted a real-time mass-spectrometry based breath profiling in hundreds of consecutive subjects under an actual respiratory infection screening scenario. Recruited subjects were grouped for further comparisons, based on multiplex-PCR confirmed infection (infected by common respiratory pathogen(s) and healthy) and presence or absence of flu like symptoms. Results Amongst recruitments, we obtained 256 healthy cases and 223 infected/coinfected (171 mono-infections, 52 coinfections) with Haemophilus influenza, Streptococcus pneumoniae and Rhinovirus. We observed multiple effects of these mono-infections and co-infections onto the exhaled VOC profiles and variations, especially on endogenous ketone, short-chain fatty acid, organosulfur, aldehyde and terpene concentrations. Based on VOCs origins, we encountered changes in patient’s energy metabolism, systemic microbial immune homeostasis, inflammation, oxidative stress and antioxidative defense. Presence of bacterial pathogens depicted more complex metabolic effects and cross-talk – most likely due to their own metabolism. Conclusion Alike our recent reports on COVID-19 and in line with other recent multi-omics and clinical microbiological reports, these results offered unique insight into common respiratory infections, pathogenesis, ‘host-microbiome-pathogen’ interactions. Breathomics depicted the non-invasive potential for ‘monitoring’ respiratory mono-infections and coinfections.