In a time when global climate variability threatens the sustainability and productivity of arid ecosystems, the development of effective strategies to recover and protect soil resources and biota is crucial for the survival of these landscapes. With 20% of arid systems degraded and estimates of up to 10 Mha of land degrading each year, this issue is of global importance. In the semi-arid Pilbara region of north-west Western Australia, climatic projections suggest reductions in annual rainfall and high unpredictability of rain events. However, as these ancient landscapes are already degraded due to meteorological processes and anthropogenic activities, such as mining, the rehabilitation of this land is severely challenging. Here, we present a case study that examines, under different rainfall scenarios, the effect of two inorganic amendments (gypsum and urea) on substrate quality and growth of two plant species (Acacia inaequilatera and Triodia wiseana) native to the Pilbara region. Through an extensive glasshouse experiment, two doses of inorganic amendments were tested and compared to unamended mining waste (overburden) substrates extracted from an iron-ore mine of moderately alkaline pH and low nitrogen status. Our results showed that the addition of urea (nitrogen-based fertiliser) produced a three-fold increase of plant growth in A. inaequilatera and up to a 25-fold increase in T. wiseana compared to unamended substrates when grown under the higher watering regime but this effect was not evident in the lower water regimes. The inorganic amendments decreased pH and increased EC, total nitrogen and N-mineralisation but did not have a significant effect on soil microbial activity. Overall, water was the dominant driver for determining the effectiveness of the substrate amendments to improve the quality of mine waste substrates and increase plant growth. This study contributes to unravelling the role of inorganic amendments in post-mining rehabilitation in arid regions faced with climate change.