Citrus Huanglongbing (HLB) is one of the most destructive diseases of citrus worldwide and is threatening the survival of the Floridian citrus industry. Currently, there is no established cure for this century-old and emerging disease. As a possible control strategy for citrus HLB, therapeutic compounds were screened using a propagation test system with ‘Candidatus Liberibacter asiaticus’-infected periwinkle and citrus plants. The results demonstrated that the combination of penicillin and streptomycin (PS) was effective in eliminating or suppressing the ‘Ca. L. asiaticus’ bacterium and provided a therapeutically effective level of control for a much longer period of time than when administering either antibiotic separately. When treated with the PS, ‘Ca. L. asiaticus’-infected periwinkle cuttings achieved 70% of regeneration rates versus <50% by other treatments. The ‘Ca. L. asiaticus’ bacterial titers in the infected periwinkle plants, as measured by quantitative real-time polymerase chain reaction, decreased significantly following root soaking or foliar spraying with PS. Application of the PS via trunk injection or root soaking also eliminated or suppressed the ‘Ca. L. asiaticus’ bacterium in the HLB-affected citrus plants. This may provide a useful tool for the management of citrus HLB and other Liberibacter-associated diseases.