Central nervous system infiltration by circulating leukemic cells and enhanced in vitro transendothelial migration of promyelocytic leukemia HL-60-derived macrophages through a blood-brain barrier model was recently demonstrated. The intrinsic molecular and signaling mechanisms involved are, however, poorly documented. Drug targeting of such translocation event performed by circulating microbes and immune cells may prevent secondary cerebral infections and development of brain pathologies. In this study, we specifically investigated the in vitro targeting efficacy of the chemopreventive and dietary-derived epigallocatechin-3-gallate (EGCG) molecule on the NF-κB-mediated transcriptional regulation of a panel of 89 biomarkers associated with promyelocytic HL-60 differentiation into macrophages. NF-κB-mediated signaling during HL-60 macrophage differentiation was reversed by EGCG, in part through reduced IκB phosphorylation and led to the inhibition of moderately to highly expressed NF-κB gene targets among which the matrix metalloproteinase (MMP)-9 and the cyclooxygenase (COX)-2. In contrast, EGCG exhibited low efficacy in reversing NF-κB-regulated genes and showed selective antagonism toward COX-2 expression while that of MMP-9 remained high in terminally differentiated macrophages. Decreased expression of the 67-kDa non-integrin Laminin Receptor in terminally differentiated macrophages may explain such differential EGCG efficacy. Our results suggest that terminally differentiated macrophage transendothelial migration associated with neuroinflammation may not be pharmacologically affected by such a specific class of flavonoid. The differentiation status of a given in vitro cell model must therefore be carefully considered for optimized assessment of therapeutic drugs.