Extreme ocean warming/cooling events in the southeast Indian Ocean off the coast of Western Australia are called Ningaloo Niño/Niña. An unprecedented Ningaloo Niño, or marine heatwave, occurred during the austral summer of 2010/2011 with mean sea surface temperatures at 3°C above the long-term mean, leading to dramatic changes in the ecosystem, such as extensive loss of kelp forest and coral bleaching. This event was attributed to a combination of an anomalous strong Leeuwin Current and high local air-sea heat fluxes. A number of local and remote forcing mechanisms have been investigated in recent years, however little is known about the depth structure and connections to large-scale ocean interannual to decadal variability. Using a suite of simulations with a high-resolution global Ocean General Circulation Model from 1958-2016, we investigate Eastern Indian Ocean variability with focus on Ningaloo Niño/Niña. In particular, we are interested in the impacts of large-scale ocean and climate variability, such as the Indonesian Throughflow and El Niño - Southern Oscillation, on the study region. Initial results show pronounced fresh anomalies associated with major heatwave events, e.g. in 2000 and 2011, coinciding with a peak in the Leeuwin Current strength. Temperature and salinity anomalies of these large events extend to over 200m depth, while some events are intensified at depth or entirely confined to the subsurface without a manifestation in SST. A unique set of sensitivity experiments allows us to distinguish the contribution of wind vs. buoyancy forcing to individual events and assess instances of reinforcing vs. compensating behaviour. Different classes of events and their forcing mechanisms are characterized. Our work can provide valuable contributions for advancing the understanding of Ningaloo Niño/Niña drivers from surface to depth and regional to large scales.