Abstract: Background and Objective: The impact of plant invasions on ecosystems, habitats and native species is severe and often irreversible. The present study attempted to observe the effect of mesquite (Prosopis juliflora) on seed germination and plant growth of two native Acacia species (Acacia ehrenbergiana and Acacia tortilis). The effect of mesquite on mutualistic interactions and soil microbial biomass was also investigated. Materials and Methods: The effect of Prosopis juliflora (P. juliflora) extract on seed germination and plant growth of two native legumes was studied in petri dish and pot experiments, respectively. Root nodule bacteria, mycorrhizal fungi and soil microbial biomass were compared between the invasive legume and two native species. Results: The results showed that different aqueous extracts of Prosopis juliflora significantly affected the germination of native Acacia species. Plant growth of these species was also affected by the litter of the invasive plant. A relationship between mutualisms and the invasion process by Prosopis juliflora has been recorded. The MPN analysis showed that the density of rhizobia organisms which were able to nodulate Prosopis juliflora was greater than for Acacia species. Arbuscular mycorrhizae fungi colonization in the roots of native species was affected by Prosopis juliflora. Conclusion: Results suggested a significant effect of Prosopis juliflora on soil microbial biomass. This is the first study reporting the relationship between invasion process of Prosopis juliflora and soil microbial community composition in Saudi Arabia.