Since European settlement Australian native rodents have experienced dramatic extinctions and declines. We investigated long-term population and distribution changes during 1981–2003, and known or potential causal factors of decline in the vulnerable New Holland mouse (Pseudomys novaehollandiae). We found that populations (n = 8) were extant for 1–6 years and were predominantly small, localised and extinction prone. High-density populations occurred after above-average rainfall but declined precipitously during drought. Wildfire resulted in the extirpation of some populations, while others survived in unburnt refugia. We propose that post-fire vegetation (3–7 years) contemporaneous with above-average rainfall delivered productive habitat resulting in both a population irruption, and recovery after wildfire. Population declines occurred in drought periods. Recent trapping at 42 sites (2013–17) failed to record any New Holland mice. The species has not been recorded since 2003. Recovery is unlikely without intensive management, focussed on remnant or reintroduced populations, including protection from habitat fragmentation and inappropriate fire regimes. Prevention of extinction of the species throughout its southern range will require similar management strategies.