Non‐steroidal anti‐inflammatory drugs (NSAIDs) have been associated with reduced risk for Alzheimer's disease (AD) and selected NSAIDs racemates suppress β‐amyloid (Aβ) accumulation in vivo and Aβ42 production in vitro. Clinical use of NSAIDs for preventing or treating AD has been hampered by dose‐limiting toxicity believed to be due to cyclooxygenase (COX)‐inhibition that is reportedly not essential for selective Aβ42 reduction. Profens have racemates and R‐enantiomers were supposed to be inactive forms. Here we demonstrate that R‐ibuprofen and R‐flurbiprofen, with poor COX‐inhibiting activity, reduce Aβ42 production by human cells. Although these R‐enantiomers inhibit nuclear factor‐κB (NF‐κB) activation and NF‐κB can selectively regulate Aβ42, Aβ42 reduction is not mediated by inhibition of NF‐κB activation. Because of its efficacy at lowering Aβ42 production and low toxicity profile, R‐flurbiprofen is a strong candidate for clinical development.