The secondary metabolite content of cranberry fruits can vary with cultivar and environmental factors, which may in turn impact their potential biological activities. To evaluate the influence of composition on anti-inflammatory activity, cranberry fruits were collected from two major U.S. growing regions. Eight extracts from these fruits were prepared, analyzed for phytochemical composition, and evaluated for their anti-inflammatory effects in human monocytes (THP-1 cells). The extracts varied widely in polyphenol and triterpenoid content. All were able to reduce lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokine interleukin 6 (IL-6) at 100 μg/mL, with inhibition ranging between 18.8 and 48.8%. Of these, three extracts high in anthocyanins, triterpenoids, or total polyphenols decreased levels of IL-6 and tumor necrosis factor alpha (TNF-α) at concentrations of 0.1–10 μg/mL compared to LPS-exposed control. Several individual cranberry phytochemicals were also capable of reducing production of IL-6, IL-1β, and TNF-α. The data suggest that phytochemicals present in varying quantities in cranberry fruits including anthocyanins, hyperoside, ursolic acid, and corosolic acid play a role in the anti-inflammatory effects of cranberry extracts on human monocytes.