In Galicia (NW Spain), ultramafic outcrops represent approximately 5% of the land surface and several mining and quarrying activities take place in these areas. Resulting mine-soils present physical, chemical and biological properties which limit plant growth and soil functioning. Nickel phytomining, an eco-friendly strategy for metal recovery, could potentially be applied to these areas. A one-year field experiment was carried out in a serpentine quarry to evaluate the performance of four Ni hyperaccumulating plant species, comparing the Mediterranean spp. Bornmuellera emarginata and Odontarrhena muralis with the native populations of Noccaea caerulescens and Odontarrhena serpyllifolia. Field plots were established and amended with inorganic NPK fertilisers or composted sewage sludge. Three replicate plots (4 m2) were planted for each plant species and fertilisation regime. Amending with compost reduced pH from 7.8 to 6.6, and increased soil cation exchange capacity (CEC), nutrient concentrations and Ni availability. Moreover, compost-amended mine-soil presented higher microbial density and activity, parameters which were further stimulated by plant growth. Plant biomass production of all plant species was significantly higher in compost-amended soils than that after NPK fertilisation, being most pronounced for O. muralis and B. emarginata. Despite the reduction in shoot Ni concentrations observed in plants (except O. muralis) grown in compost-amended plots, the increased biomass production led to significantly higher Ni yields (in kg ha−1) in B. emarginata (2.9), N. caerulescens (1.9) and O. muralis (2.3). All plant species were able to establish and grow in the mine-soil (with the Mediterranean species showing a higher capacity for adaptation) and to generate moderate Ni yields. Nonetheless, the results highlight the need for further optimisation in order to enhance the Ni phytoextraction efficiency. Finally, the improvement in soil quality after compost amendment and plant growth support the idea that phytomining systems can be effective approaches for the rehabilitation of soils affected by quarrying operations after mine closure.