Acid rain has many negative effects on the ecological environment and poses serious abiotic stress onto plants, resulting in substantial ecological and economic impairments annually. Ilex chinensis, a well-known medicinal plant, is sensitive to acid rain, but its response mechanisms are unclear. In this study, we simulated sulfuric acid rain (SAR), mixed acid rain (MIX), and nitric acid rain (NAR) at different pH values to investigate their effects on growth condition, photosynthesis, antioxidants, and nitrogen metabolites. We also explored the metabolic pathways and key genes involved in the response of I. chinensis to acid rain through transcriptome analysis. Physiological analysis showed that I. chinensis suffered the most significant inhibition at pH 3.0, which is manifested in the decrease in height growth rate, specific leaf weight, photosynthetic pigments content, net photosynthetic rate, stomatal conductance, and transpiration rate; the increase in MDA content and SOD activity; and the reduction in glutamine synthetase activity, nitrogen content, and proline content. Transcriptome analysis isolated 314 and 21 shared differentially expressed genes (DEGs) from I. chinensis treated with acid rain at pH 3.0 for 5 d and 15 d, respectively. KEGG enrichment analysis found that different types of acid rain caused changes in multiple metabolic pathways of I. chinensis, and the shared DEGs in 5 d treatment were mainly enriched in ribosomes, oxidative phosphorylation, and glycolysis/glycolysis, etc. The shared DEGs in 115 d treatment were mainly enriched in sulfur metabolism, RNA polymerase, cysteine and methionine metabolism, etc. Further research on gene regulatory networks at the two time points showed that the key pathways of I. chinensis, in response to acid rain stress, include plant–pathogen interaction, MAPK signaling pathway-plant, protein processing in the endoplasmic reticulum, ubiquitin mediated proteolysis, etc., in which 6 hub genes were identified, including TRINITY_DN13584_c0_g1, TRINITY_DN164_c0_g4, TRINITY_DN654_c0_g1, TRINITY_DN13611_c1_g2, TRINITY_DN21290_c0_g2, TRINITY_DN44216_c0_g1. Our findings provide a basis for exploring the regulatory mechanisms of I. chinensis in response to acid rain at the physiological and molecular levels, and for identifying candidate genes with acid tolerance potential.