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Coffee extracts contain numerous bioactive compounds. Given the dietary link between coffee consumption and colorectal cancer, this study compared the effects of roasted and green (unroasted) coffee extracts on human colorectal cancer cells (HCT116) and non-cancerous fibroblasts (BJ-5ta) to evaluate how processing influences proliferation and molecular signaling. Real-time cell analysis (RTCA), qRT-PCR, and label-free quantitative proteomic analysis were performed to assess cellular responses. MTS and RTCA showed that in BJ-5Ta fibroblasts, coffee extracts increased proliferation in the order CNR < CAR < CAU < CNU, whereas the trend was reversed in HCT116 cancer cells. Proteomic analysis revealed that in BJ-5Ta cells, unroasted coffee extract caused downregulation of the ribosome pathway, and natural coffee extract caused downregulation of the gap junction pathway, indicating reduced protein synthesis and cell-cell communication as a potential stress-adaptive response. In contrast, in HCT116 cells, unroasted coffee extract upregulated the ribosome pathway. Also, natural coffee extract upregulated the pentose phosphate pathway in HCT116 cells, which may enhance NADPH production and reduce oxidative stress. Current evidence suggests coffee's bioactive compounds may have different effects varying by coffee extract type and their preparation.