Context Cancer bush (Lessertia frutescens L.) is a multipurpose medicinal legume endemic to southern Africa, reported to grow in a variety of soils, from very poor to fertile ones. However, there is limited knowledge on how L. frutescens is able to thrive in diverse soils and, particularly, nothing has been reported on the benefits from the microbe symbiosis, plant growth and acclimation to low nutrient soils. Aims Therefore, this study examined the effect of soil nutrient deficiency in plant–microbe symbiosis, nitrogen (N) nutrition and associated plant performance of L. frutescens plants, growing in four different impoverished soils from the KwaZulu-Natal region. Methods Experimental soil samples collected from four geographical distinct KwaZulu-Natal (KZN) locations (Hluhluwe, Izingolweni, Bergville and Ashburton) representing grasslands and savanna were used as natural inoculum and growth substrate. Key results Soil analysis showed significant differences in soil pH, exchange acidity, total cations, organic carbon (C), phosphorus (P) and N related to differences in the soil provenance. L. frutescens root nodules were dominated by Bacillus sp. in all soil treatments, except in plants grown in Bergville soil that did not nodulate. In all, 68–90% of total plant N concentration was reduced from atmospheric N. L. frutescens plants also relied on soil-available N for growth. Hluhluwe and Ashburton soil-grown plants showed a significantly higher biomass than did other soil-grown plants. Conclusions These current findings demonstrated that L. frutescens root nodules were dominated by bacteria characterised as phospho-bacteria and N2-fixing bacteria in these impoverished soils. This enabled L. frutescens to fix atmospheric N and assimilate soil available N to reduce energy demand. Implications These strategies may collectively contribute to L. frutescens resilience in nutrient-deficient savanna and grassland ecosystems.