Ca
2+
-activated BK channels in renal intercalated cells (ICs) mediate luminal flow–induced K
+
secretion (FIKS), but how ICs sense increased flow remains uncertain. We examined whether PIEZO1, a mechanosensitive Ca
2+
-permeable channel expressed in the basolateral membranes of ICs, is required for FIKS. In isolated cortical collecting ducts (CCDs), the mechanosensitive cation-selective channel inhibitor GsMTx4 dampened flow-induced increases in intracellular Ca
2+
concentration ([Ca
2+
]
i
), whereas the PIEZO1 activator Yoda1 increased [Ca
2+
]
i
and BK channel activity. CCDs from mice fed a high-K
+
(HK) diet exhibited a greater Yoda1-dependent increase in [Ca
2+
]
i
than CCDs from mice fed a control K
+
diet. ICs in CCDs isolated from mice with a targeted gene deletion of
Piezo1
in ICs (IC-
Piezo1
-KO) exhibited a blunted [Ca
2+
]
i
response to Yoda1 or increased flow, with an associated loss of FIKS in CCDs. Male IC-
Piezo1
-KO mice selectively exhibited an increased blood [K
+
] in response to an oral K
+
bolus and blunted urinary K
+
excretion following a volume challenge. Whole-cell expression of BKα subunit was reduced in ICs of IC-
Piezo1
-KO mice fed an HK diet. We conclude that PIEZO1 mediates flow-induced basolateral Ca
2+
entry into ICs, is upregulated in the CCD in response to an HK diet, and is necessary for FIKS.