Lung cancer is responsible for the highest rate of cancer mortality worldwide. Lung cancer patients are often ineligible for tumour biopsies due to co-morbidities. As a result, patients may not have the most effective treatment regimens administered. Patients with mutations in the epidermal growth factor receptor (EGFR) have improved survival in response to EGFR tyrosine kinase inhibitors (TKIs). A non-invasive method of determining EGFR mutations in patients would have promising clinical applications. Exosomes have the potential to be non-invasive novel diagnostic markers in cancer. Using mass spectrometry analysis, we identify differentially abundant cell and exosome proteins induced by mutations in p53 and EGFR in lung cells. Importantly, mutations in p53 and EGFR alter cell and exosome protein content compared to an isogenic normal lung epithelial cell. For some proteins, mutation had similar effects in the cell of origin and exosomes. Differences between the cells of origin and exosomes were also apparent, which may reflect specific packaging of proteins into exosomes. These findings that mutations alter protein abundance in exosomes suggest that analysis of exosomes may be beneficial in the diagnosis of oncogenic mutations.