Triple-negative breast cancer (TNBC) is an aggressive and difficult to treat subtype of breast cancer. Cancer mortality is due to disseminated disease that has become resistant to multiple therapeutic modalities. Nonspecific cytotoxic agent paclitaxel (PTX) is a standard of care, although its treatment is associated with severe side effects and the acquisition of chemoresistance. We have recently demonstrated the expression of histamine H3 receptor (H3R) in TNBC samples and the antitumoral efficacy and safety of the LINS01 series of H3R antagonists in TNBC experimental models. The aim of this work was to evaluate whether LINS01022 and LINS01023 compounds could potentiate PTX therapy in 4T1 TNBC cells and in PTX-resistant 4T1 cells (4T1 R). 4T1 cells were exposed to increasing concentrations of PTX until resistance was acquired. The expression of H3R in 4T1 R was confirmed through immunocytochemistry. Both LINS01022 and LINS01023 compounds produced a dose-dependent inhibition of clonogenic proliferation in 4T1 R, demonstrating low IC50 values (3.2 and 0.9 µM, respectively), exhibiting an even more potent antiproliferative effect than the one observed in the respective 4T1 parental cells. Both LINS01022 and LINS01023 potentiated PTX-induced reduction of cell proliferation and viability in both 4T1 R and 4T1 parental cells. Multidrug resistance-1 (MDR1) acts as a chemotherapeutic drug efflux pump that is involved in chemoresistance of tumor cells. An increased expression of MDR1 was observed in 4T1 R cells. The efflux modulating effects of LINS01 compounds were investigated using the rhodamine 123 accumulation assay. Interestingly, LINS01 compounds showed a potent MDR1 efflux pump inhibitory action in 4T1 R cells, which contributes to overcoming PTX resistance. We conclude that H3R antagonists LINS01 might be potential therapeutic candidates against TNBC with the capacity to reverse PTX resistance.