Substance use disorder (SUD) is a complex process in which several neurocircuits are disturbed and various brain regions are involved. The amygdala is a region that mediates the withdrawal effect as well as anxiety and depression-like behaviors. However, the specific transcriptional changes in each cell type during SUD is largely unknown. Here we performed single-cell RNA sequencing and classified all cell types in mouse amygdala under opioid dependence and withdrawal conditions. Our data revealed key biological processes, such as immune response, inflammation, synaptic transmission, and mitochondrial respiration, changed in a distinct manner in different cell populations. Dramatic differences were unraveled in the transcriptional profiles between dependence and withdrawal states. Overall, our work has provided a comprehensive dataset of genes, biological pathways and cell-cell interactions for all the identified cell types in the amygdala, thus expanding our limited understanding of brain alterations during SUD, especially at the molecular and cellular levels.