Histone deacetylation plays an important role in epigenetic control of gene expression. HD2 is a plant-specific histone deacetylase that is able to mediate transcriptional repression in many biological processes. To investigate the epigenetic and transcriptional mechanisms of longan fruit senescence, one histone deacetylase 2-like gene, DlHD2, and two ethylene-responsive factor-like genes, DlERF1 and DlERF2, were cloned and characterized from longan fruit. Expression of these genes was examined during fruit senescence under different storage conditions. The accumulation of DlHD2 reached a peak at 2 d and 30 d in the fruit stored at 25 °C (room temperature) and 4 °C (low temperature), respectively, or 6 h after the fruit was transferred from 4 °C to 25 °C, when fruit senescence was initiated. However, the DlERF1 transcript accumulated mostly at the later stage of fruit senescence, reaching a peak at 5 d and 35 d in the fruit stored at 25 °C and 4 °C, respectively, or 36 h after the fruit was transferred from low temperature to room temperature. Moreover, application of nitric oxide (NO) delayed fruit senescence, enhanced the expression of DlHD2, but suppressed the expression of DlERF1 and DlERF2. These results indicated a possible interaction between DlHD2 and DlERFs in regulating longan fruit senescence, and the direct interaction between DlHD2 and DlERF1 was confirmed by yeast two-hybrid and bimolecular fluorescence complementation (BiFC) assays. Taken together, the results suggested that DlHD2 may act with DlERF1 to regulate gene expression involved in longan fruit senescence.