Modulation of microglial response could be a target to reduce neuroinflammation associated with Alzheimer's disease. In this study, we propose that lipophilic bioactive molecules present in pomace olive oil (POO), transported in triglyceride-rich lipoproteins (TRLs), are able to modulate microglial high-oleic sunflower oil (HOSO, points) or pomace olive oil (POO, stripes). In order to prove this hypothesis, a randomized crossover postprandial trial was performed in 18 healthy young women. POO was assayed in opposition to high-oleic sunflower oil (HOSO), a common dietary oil which shares with POO an almost identical fatty acid composition but lacks certain biomolecules with recognized antioxidant and anti-inflammatory activities. TRLs were isolated from blood at the baseline and 2 and 4 hours postprandially and used to treat BV-2 cells to assess their ability to modulate the microglial function. We found that the intake of POO leads to the constitution of postprandial TRLs that are able to modulate the inflammatory response in microglia compared to HOSO. TRL-derived POO reduced the release of pro-inflammatory cytokines (tumor necrosis factor-α, and interleukins 1β and 6) and nitric oxide and downregulated genes codifying for these cytokines and inducible nitric oxide synthase (iNOS) in BV-2 cells. Moreover, the ingestion of POO by healthy women slightly improved glycemic control and TRL clearance throughout the postprandial phase compared to HOSO. In conclusion, we demonstrated that consuming POO results in postprandial TRLs containing lipophilic bioactive compounds capable of regulating the inflammatory response prompted by microglial activation.