Coffee consumption is correlated with a lower risk for type 2 diabetes mellitus (T2D), though whether differences exist in the T2D-mitigating bioactivities of decaffeinated (RD) and regular (RR) coffee is unclear. We conducted cell-based experiments to determine whether different phenolic levels in RD and RR affect T2D-mitigating bioactivities. The total phenolic content and the chemical antioxidant activity were significantly higher in RD than RR. However, these coffees had comparable cellular antioxidant activity. Both coffees reduced activation of NF-κB, with RR being twice as strong as RD. They also both increased glucose uptake in human adipocytes by 2-fold. Of the bioactivities examined, only chemical antioxidant activity was related to total phenolic levels. The NF-κB inhibition was proportional to chlorogenic acid levels, though chlorogenic acids could not account for the full inhibitory effect of coffee. Thus, a matrix effect may exist, whereby components of coffee work together to provide bioactivities that ameliorate the T2D risk.