The opportunistic pathogen Burkholderia cenocepacia is a ubiquitous environmental Gram-negative species associated with severe and persistent Cystic Fibrosis (CF) infections. Within CF patients B. cenocepacia colonises the lungs establishing an intracellular replicative niche within macrophages. While the importance of macrophages for persistent infections is established, how B. cenocepacia manipulates macrophages as well as the changes within B. cenocepacia required for intracellular replication are unclear. A key limitation for understanding the intracellular replication of B. cenocepacia has been the low infectivity of B. cenocepacia resulting in highly heterogenous infections dominated by uninfected cells within in vitro models. Using opsonization to increase the uptake of B. cenocepacia into THP-1 macrophages we have established a model to improve the uniformity of B. cenocepacia internalisation allowing proteomic analysis of B. cenocepacia infections. Using DIA proteomics, we compare the impact of opsonization on the host response and our ability to monitor intracellular B. cenocepacia. We observed opsonization improves the detection of proteomic changes in response to B. cenocepacia compared to non-opsonized infection leading to a 75% increase in the host proteins detected to be differentially impacted during B. cenocepacia infection. Importantly, we see the host proteome changes strongly correlate between infection with and without opsonization supporting opsonisation itself does not change the nature of the response but enhances the magnitude. While at 3hr post infection we observed relatively few proteome alterations within the THP-1 proteome, by 24hr post infection a robust response is observed within cytokine and interferon signalling pathways including several host proteins associated with immune evasion such as KDM6B, ILI41 and IFI44. Excitingly opsonization does not only improve the detection of host changes but dramatically improves detection of B. cenocepacia proteins revealing dramatic changes in metabolic proteins in response to intracellular replication. To further understand these changes coupling DIA proteomics with crude isolation of intracellular bacteria enabled the quantification of more than 2000 bacterial proteins supporting changes in the B. cenocepacia proteome from early and late stage of infection. Our study is the first to provide a comprehensive profile of both host and pathogen proteome changes during B. cenocepacia infection in macrophage cells shedding light on the fine-tuning of bacterial metabolism employed by intracellular B. cenocepacia.