Plant growth-promoting rhizobacteria (PGPR) have been collected and used to promote plant growth and enhance disease tolerance of various crops. In the current work, Pseudomonas aeruginosa CAKS2, an endophytic strain isolated from the rhizosphere of sweet orange, exhibited both growth promotion and antimicrobial activities. Under the in vitro condition, the CAKS2 showed multiple plant growth-promoting properties such as phosphate, potassium, and calcium solubilization, nitrogen fixation as well as production of siderophores, IAA, ammonia, exopolysaccharides, hydrogen cyanide, and biofilm formation. This P. aeruginosa strain inhibited the growth of different tested fungal and bacterial pathogens. Under the in vivo condition, the CAKS2 enhanced sweet orange plant growth, indicated by increases in the root and shoot lengths, the leaf number, and the total biomass. The biochemical components and the transcription levels of genes related to plant hormone biosynthesis were altered in the CAKS2-inoculated sweet orange. Under the in vivo infection of C. gloeosporioides, the CAKS2 reduced the diameter of lesions on orange leaves and harvested fruits and decreased disease severity and incidence at the whole plant level. The whole genome sequence of CAKS2 showed the presence of candidate genes involved in different molecular pathways contributing to plant-promoting and biocontrol properties. Importantly, certain changes in the expression of gene response for plant growth promotion and biocontrol were observed when the CAKS2 was exposed to sweet orange root exudates. This study highlights P. aeruginosa CAKS2 as a potential PGPR strain for enhancing plant growth and C. gloeosporioides tolerance in sweet orange and other citrus plants.