P-glycoprotein (P-gp) is a pump that reduces xenobiotics’ accumulation inside cells, and its activity can be modulated by inhibitors, inducers and activators. The first ones have been used to counteract the multidrug resistance (MDR) phenomena, and the inducers and activators have been proposed as a therapeutic approach in intoxication scenarios. P-gp binds several unrelated hydrophobic drugs, and its activity can be modified to increase or decrease drug intracellular accumulation. Previous in vitro studies showed that fiscalins, marine-derived compounds, can alter P-gp transport activity in differentiated neuronal SH-SY5Y cells. Some fiscalin derivatives showed to act as inhibitors, whether others were activators of P-gp expressed in these cells. Considering the fact that P-gp is a major efflux pump expressed in barrier tissues, influencing xenobiotics’ pharmacokinetics and bioavailability, the main aim of this work is to explore the effects of some fiscalins as potential modulators of P-gp at the intestinal barrier, which could be a useful tool to counteract MDR, or to reduce the toxicity mediated by xenobiotics as a result of reducing their absorption.