Background: Cadmium (Cd) pollution of soils is a global concern because its accumulation in plants generates severe growth retardation and health problems. Hibiscus syriacus is an ornamental plant that can tolerate various abiotic stresses, including Cd stress. Therefore, it is proposed as a plant material in Cd-polluted areas. However, the molecular mechanisms of H. syriacus tolerance to Cd are not yet understood. Results: This study investigated the physiological and transcriptional response of “Hongxing”, a Cd2+-tolerant H. syriacus variety, grown on a substrate containing higher concentration of Cd (400 mg/kg). The Cd treatment induced only 28% of plant mortality, but a significant decrease in the chlorophyll content was observed. Malondialdehyde content and activity of the antioxidant enzymes catalase, peroxidase, and superoxide dismutase were significantly increased under Cd stress. Transcriptome analysis identified 29,921 differentially expressed genes (DEGs), including 16,729 down-regulated and 13,192 up-regulated genes, under Cd stress. Functional enrichment analyses assigned the DEGs mainly to plant hormone signal transduction, transport, nucleosome and DNA processes, mitogen-activated protein kinase signaling pathway, antioxidant process, fatty acid metabolism, and biosynthesis of secondary metabolites. Many MYB, EP2/ERF, NAC, WRKY family genes, and genes containing metal binding domains were up-regulated, implying that they are essential for the Cd-stress response in H. syriacus. The most induced genes were filtered out, providing valuable resources for future studies. Conclusions: Our findings provide insights into the molecular responses to Cd stress in H. syriacus. Moreover, this study offers comprehensive and important resources for future studies toward improving the plant Cd tolerance and its valorization in phytoremediation.