Lactobacillus delbrueckii subsp. bulgaricus is currently one of the most valuable lactic acid bacteria (LAB) and widely used in global dairy industry. The acid tolerance and adaptation ability of LAB is the key point of their survival and proliferation during fermentation process and in gastrointestinal tract of human body. Two component system (TCS) is one of the most important mechanisms to allow bacteria to sense and respond to changes of environmental conditions. TCS typically consists of a histidine protein kinase (HPK) and a corresponding response regulator (RR). Our previous study indicated a TCS (JN675228/JN675229) was involved in acid adaptation in L. bulgaricus. To reveal the role of JN675228 (HPK1)/JN675229 (RR1) in acid adaptation, the target genes of JN675228 (HPK1)/JN675229 (RR1) were identified by means of a proteomic approach complemented with transcription data in the present study. The results indicated that HPK1/RR1 regulated the acid adaptation ability of bacteria by means of many pathways, including the proton pump related protein, classical stress shock proteins, carbohydrate metabolism, nucleotide biosynthesis, DNA repair, transcription and translation, peptide transport and degradation, and cell wall biosynthesis, etc. To our knowledge, this is the first report with the effect of acid adaptation-related TCS HPK1/RR1 on its target genes. This study will offer experimental basis for clarifying the acid adaptation regulation mechanism of L. bulgaricus, and provide a theoretical basis for this bacterium in industry application.