Cell size is tightly controlled in healthy tissues, but it is poorly understood how variations in cell size affect cell physiology. To address this, we employed a high-accuracy mass spectrometry-based approach to measure how the proteome changes with cell size. Protein concentration changes are widespread, measurable in both asynchronous and G1-arrested cell populations, and predicted by subcellular localization, size-dependent changes in mRNA concentrations, and protein turnover. As proliferating cells grow larger, protein concentration changes typically associated with cellular senescence are increasingly pronounced. This suggests that large size is a cause rather than just a consequence of cell senescence. Consistent with this hypothesis, larger cells are prone to replicative, DNA damage-, and CDK4/6i-induced senescence. Size-dependent changes to the proteome, including those associated with senescence, are not observed when an increase in cell size is accompanied by a similar increase in ploidy. This shows that proteome composition is determined by the DNA-to-ploidy ratio rather than cell size per se and that polyploidization is an elegant method to generate large non-senescent cells as is commonly found in nature. Together, our findings show how cell size could impact many aspects of cell physiology through remodeling the proteome, thereby providing a rationale for cell size control and polyploidization.