Diarrhea is one of the most commonly reported adverse effect of hemotherapy and targeted cancer therapies, such as tyrosine kinase inhibitors (TKI), which often significantly impact patient quality of life, morbidity, and mortality. Neratinib is an oral, irreversible pan‐HER tyrosine kinase inhibitor, which is clinically active in HER2‐positive breast cancer. Diarrhea is the most common side effect of this potent anticancer drug and the reasons for this adverse effect are still largely unclear. We have recently shown that activation of the calcium‐sensing Receptor (CaSR) can inhibit secretagogue‐induced diarrhea in the colon, therefore we hypothesized that CaSR activation may also mitigate neratinib‐induced diarrhea. Using an established ex vivo model of isolated intestinal segments, we investigated neratinib‐induced fluid secretion and the ability of CaSR activation to abate the secretion. In our study, individual segments of the rat intestine (proximal, middle, distal small intestine, and colon) were procured and perfused intraluminally with various concentrations of neratinib (10, 50, 100 nmol L⁻¹). In a second set of comparison experiments, intraluminal calcium concentration was modulated (from 1.0 to 5.0 or 7.0 mmol L⁻¹), both pre‐ and during neratinib exposure. In a separate series of experiments R‐568, a known calcimimetic was used CaSR activation and effect was compared to elevated Ca²⁺ concentration (5.0 and 7.0 mmol L⁻¹). As a result, CaSR activation with elevated Ca²⁺ concentration (5.0 and 7.0 mmol L⁻¹) or R‐568 markedly reduced neratinib‐induced fluid secretion in a dose‐dependent manner. Pre‐exposure to elevated luminal calcium solutions (5.0 and 7.0 mmol L⁻¹) also prevented neratinib‐induced fluid secretion. In conclusion, exposure to luminal neratinib resulted in a pronounced elevation in fluid secretion in the rat intestine. Increasing luminal calcium inhibits the neratinib‐associated fluid secretion in a dose‐dependent manner. These results suggest that CaSR activation may be a potent therapeutic target to reduce chemotherapy‐associated diarrhea.