The present study evaluated the effects of in vitro maturation (IVM) on the proteome of cumulus–oocyte complexes (COCs) from ewes. Extracted COC proteins were analyzed by LC‐MS/MS. Differences in protein abundances (p < 0.05) and functional enrichments in immature versus in vitro‐matured COCs were evaluated using bioinformatics tools. There were 2550 proteins identified in the COCs, with 89 and 87 proteins exclusive to immature and mature COCs, respectively. IVM caused downregulation of 84 and upregulation of 34 proteins. Major upregulated proteins in mature COCs were dopey_N domain‐containing protein, structural maintenance of chromosomes protein, ubiquitin‐like modifier‐activating enzyme 2. Main downregulated proteins in mature COCs were immunoglobulin heavy constant mu, inter‐alpha‐trypsin inhibitor heavy chain 2, alpha‐2‐macroglobulin. Proteins exclusive to mature COCs and upregulated after IVM related to immune response, complement cascade, vesicle‐mediated transport, cell cycle, and extracellular matrix organization. Proteins of immature COCs and downregulated after IVM were linked to metabolic processes, immune response, and complement cascade. KEGG pathways and miRNA‐regulated genes attributed to downregulated and mature COC proteins related to complement and coagulation cascades, metabolism, humoral response, and B cell‐mediated immunity. Thus, IVM influenced the ovine COC proteome. This knowledge supports the future development of efficient IVM protocols for Ovis aries. In vitro maturation (IVM) alters the proteome of cumulus–oocyte complexes (COC) from adult ewes. Major protein signatures characterizing mature COCs relate to immune response, complement cascade, vesicle‐mediated transport, cell cycle, extracellular matrix organization and metabolism, among other events. Knowledge of COC protein atlas will certainly improve IVM protocols. Created with BioRender.com.