Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids is a promising approach. The di-tert-butylphenol derivativesR-830,S-2474,KME-4, andE-5110represent potent dual COX-2/5-LO inhibitors. The incorporation ofp-carborane and further substitution of thep-position resulted in four carborane-based di-tert-butylphenol analogs that showed no or weak COX inhibition but high 5-LO inhibitory activities in vitro. Cell viability studies on five human cancer cell lines revealed that thep-carborane analogsR-830-Cb,S-2474-Cb,KME-4-Cb, andE-5110-Cbexhibited lower anticancer activity compared to the related di-tert-butylphenols. Interestingly,R-830-Cbdid not affect the viability of primary cells and suppressed HCT116 cell proliferation more potently than its carbon-basedR-830counterpart. Considering all the advantages of boron cluster incorporation for enhancement of drug biostability, selectivity, and availability of drugs,R-830-Cbcan be tested in further mechanistic and in vivo studies.