Key miRNAs including sbi-miR169p/q, sbi-miR171g/j, sbi-miR172a/c/d, sbi-miR172e, sbi-miR319a/b, sbi-miR396a/b, miR408, sbi-miR5384, sbi-miR5565e and nov_23 were identified to function in the regulation of Cd accumulation and tolerance. As an energy plant, sweet sorghum shows great potential in the phytoremediation of Cd-contaminated soils. However, few studies have focused on the regulatory roles of miRNAs and their targets under Cd stress. In this study, comparative analysis of sRNAs, degradome and transcriptomics was conducted in high-Cd accumulation (H18) and low-Cd accumulation (L69) genotypes of sweet sorghum. A total of 38 conserved and 23 novel miRNAs with differential expressions were identified under Cd stress or between H18 and L69, and 114 target genes of 41 miRNAs were validated. Furthermore, 25 miRNA-mRNA pairs exhibited negatively correlated expression profiles and sbi-miR172e together with its target might participate in the distinct Cd tolerance between H18 and L69 as well as sbi-miR172a/c/d. Additionally, two groups of them: miR169p/q-nov_23 and miR408 were focused through the co-expression analysis, which might be involved in Cd uptake and tolerance by regulating their targets associated with transmembrane transportation, cytoskeleton activity, cell wall construction and ROS (reactive oxygen species) homeostasis. Further experiments exhibited that cell wall components of H18 and L69 were different when exposed to cadmium, which might be regulated by miR169p/q, miR171g/j, miR319a/b, miR396a/b, miR5384 and miR5565e through their targets. Through this study, we aim to reveal the potential miRNAs involved in sweet sorghum in response to Cd stress and provide references for developing high-Cd accumulation or high Cd-resistant germplasm of sweet sorghum that can be used in phytoremediation.