There is emerging consensus that P2X₄ and P2X₇ ionotropic purinoceptors (P2X₄R and P2X₇R) are critical players in regulating [Ca²⁺]i dynamics and fluid secretion in the salivary gland. In contrast, details regarding their compartmentalization and selective activation, contributions to the spatiotemporal properties of intracellular signals and roles in regulating protein exocytosis and ion channel activity have remained largely undefined. To address these concerns, we profiled mouse parotid acinar cells using live-cell imaging to follow the spatial and temporal features of ATP-evoked Ca²⁺ dynamics and exocytotic activity. Selective activation of P2X7Rs revealed an apical-to-basal [Ca²⁺]i signal that initiated at the sub-luminal border and propagated with a wave speed estimated at 17.3 ± 4.3 μm s⁻¹ (n =6). The evoked Ca²⁺ spike consisted of Ca²⁺ influx and Ca²⁺-induced Ca²⁺ release from intracellular Ca²⁺ channels. In contrast, selective activation of P2X₄Rs induced a Ca²⁺ signal that initiated basally and propagated toward the lumen with a wave speed of 4.3 ± 0.2 μm s⁻¹ (n =8) that was largely independent of intracellular Ca²⁺ channel blockade. Consistent with these observations, P2X₇R expression was enriched in the sub-luminal regions of acinar cells while P2X₄R appeared localized to basal areas. In addition, we showed that P2X₄R and P2X₇R activation evokes exocytosis in parotid acinar cells. Our studies also demonstrate that the P2X₄R-mediated [Ca²⁺]i rise and subsequent protein exocytosis was enhanced by ivermectin (IVR). Thus, in addition to furthering our understanding of salivary gland physiology, this study identifies P2X₄R as a potential target for treatment of salivary hypofunction diseases.