The single-event response of a three-layer heterogeneously integrated commercial off-the-shelf (COTS) CMOS image sensor (CIS) to alpha particles of different energies is analyzed. The energies of the alpha particles are selected, such that they stop in two separate functional layers of the device-under-test (DUT). Differences in the single-event response of the DUT depend on alpha particle energy. Spatial profiling of ionizing events reveals susceptibility in the peripheral circuitry of the dynamic random-access memory (DRAM) layer to single-event functional interrupts (SEFIs). The on-chip demosaicing algorithm contributes significantly to the number of pixels affected by transient-ionizing events. Large groupings of affected pixels are manifestations of ionizing events in the peripheral circuitry contained within the image-sensitive layer of the DUT. Similarities in the captured data sets reveal the single-event response of the pixel layer dominates the system-level response of the DUT.