Bauer alkylamide 11 and Bauer ketone 23 were previously found to be partially responsible forEchinacea angustifolia anti-inflammatory properties. This study further tested their importance using the inhibition of prostaglandin E2 (PGE2) and nitric oxide (NO) production by RAW264.7 mouse macrophages in the absence and presence of lipopolysaccharide (LPS) and E. angustifolia extracts, phytochemical enriched fractions, or pure synthesized standards. Molecular targets were probed using microarray, qRT-PCR, Western blot, and enzyme assays. Fractions with these phytochemicals were more potent inhibitors of LPS-induced PGE2 production than E. angustifolia extracts. Microarray did not detect changes in transcripts with phytochemical treatments; however, qRT-PCR showed a decrease in TNF-α and an increase of iNOS transcripts. LPS-induced COX-2 protein was increased by an E. angustifolia fraction containing Bauer ketone 23 and by pure phytochemical. COX-2 activity was decreased with all treatments. The phytochemical inhibition of PGE2 production byEchinacea may be due to the direct targeting of COX-2 enzyme.