Extreme events are often attributable to the compounding effects of anthropogenic warming and natural variability. Marine cloud brightening (MCB), a solar geoengineering proposal to reduce long-term warming, could theoretically mitigate extremes by instead targeting seasonal-to-multiyear phenomena, such as El Niño–Southern Oscillation (ENSO). Yet the effectiveness of regional MCB to deliberately modify ENSO has not been tested. By exploiting the 2019–2020 Australian wildfire opportunistic experiment, we demonstrate that the “natural” cloud brightening and ensuing La Niña–like response can be reproduced by simulating MCB in the southeast Pacific. We then explore how MCB modifies the 1997–1998 and 2015–2016 El Niño events. MCB initiated during the El Niño growth phase disrupts the Bjerknes feedbacks that normally amplify El Niño conditions, but those effects weaken after MCB is terminated. Only the earliest and longest interventions restore neutral ENSO conditions and weaken teleconnections. Weakening El Niño can result in unintended consequences including an earlier La Niña following the targeted El Niño, although early and short interventions may counter these effects. Our results support the consideration of climate variability and teleconnections as targets in solar geoengineering research.