This dataset comprises whole-proteome quantitative mass spectrometry analyses using TMT-16plex labeling to compare Toxoplasma gondii parasites expressing wild-type (cWT) or RNA-binding-deficient mutant (cMUT) forms of TgPRO — a CCCH-type zinc finger RNA-binding protein — grown under ambient (21%) and reduced (1%) oxygen conditions. TgPRO was identified in a genome-wide CRISPR screen as required for parasite fitness at high density, and loss of TgPRO selectively impairs parasite fitness at high density under ambient oxygen conditions, accompanied by elevated reactive oxygen species, mitochondrial dysfunction, and broad metabolic dysregulation. This proteomic dataset provides an unbiased view of the protein-level changes driven by TgPRO activity and oxygen availability, supporting the role of TgPRO in regulating transcripts involved in iron-sulfur cluster assembly and carbon metabolism, and can be further utilized to explore additional TgPRO-dependent targets and the broader proteomic response of T. gondii to hypoxia.