The increasing package-level integrations of high-power-density electronics, combined with system-level mounting constraints in practical hardware platforms, are driving the need for large-footprint heat sinks, which can maintain high cooling performance in both horizontal- and vertical-mounting configuration. However, the flow boiling behavior under vertical-mounting configuration, with a vertically oriented heated surface and horizontally aligned flow channels, is still unclear. In this study, flow boiling of R134a was experimentally investigated in a large-footprint (68 mm × 80 mm) heat sink under vertical-mounting conditions at mass fluxes of 103 and 180 kg/m2·s, heat fluxes of 17–207 kW/m2, and an inlet subcooling of 10 °C. Temperature measurements and high-speed flow visualization were employed to examine the effects of buoyancy, outlet-port arrangement, and parallel channel instability (PCI) on vapor transport and rewetting dynamics. The results reveal that buoyancy-induced vapor accumulation is the primary cause of local dryout and thermal nonuniformity, producing temperature differences of up to 11.3 °C across the heated surface. Relocating the outlet port toward the upper region of the heat sink facilitates vapor discharge along the buoyancy direction and partially alleviates vapor accumulation. More importantly, PCI was found to induce periodic flow redistribution and accelerated liquid-wave propagation, resulting in intermittent rewetting of dryout regions and suppression of vapor blanketing. High-speed visualization directly captured the PCI-assisted rewetting process and showed that PCI could self-regulate to variations in heat flux, plenum size, mass flux and outlet port configuration, thereby maintaining sufficient local mixture velocity for vapor removal and reducing temperature nonuniformity by 7 °C. The results provide new insights into the interplay between flow instability and rewetting, while establishing that PCI, traditionally regarded as detrimental, can play a beneficial role in large-footprint two-phase cooling systems under vertical-mounting configurations.