Global change pressures influence estuarine functionality, driving structural shifts that threaten ecosystem resilience. Estuarine lakes are inherently susceptible to these pressures given their tendency to experience prolonged periods of water residency and mouth closure. As such, this study aimed to investigate water quality and phytoplankton responses to drastic shifts in abiotic conditions during the transition from a dry to wet cycle in the Verlorenvlei Estuarine Lake, South Africa. Initially, drought- and human-induced hydrological constraints resulted in extreme environmental conditions, characterised by low water levels and acidification. These low water levels reduced connectivity, resulting in hypersaline conditions and phytoplankton blooms (>20 μg Chl-a L−1) in the lower reaches, while the main basin became brackish, highly acidic (pH < 4), and ammonium-rich (>10 mg/L). Conversely, increased flow improved connectivity, although the lower reaches remained hypersaline and pH in the main basin remained low. When the mouth was open, conditions became homogenous and oligohaline, with neutralised pH levels (>6.5) and low phytoplankton biomass (<5 μg Chl-a L−1). Upon mouth closure, the lower reaches shifted to mesohaline conditions, the main basin became acidic (pH < 5) and supported high-biomass (>60 μg Chl-a l−1) bloom conditions of non-siliceous taxa, and the upper reaches became disconnected. As such, it is critical for catchment-scale interventions to be implemented that conserve and restore freshwater inflow to dilute acidity and replenish the buffering capacity of the system. Without intervention, ongoing anthropogenic and climate change stressors may push the system towards an irreversible ecological tipping point.