Pinellia ternata (Thunb.) Breit is a member of the Araceae family and is globally distributed. The dry tuber has been used as a traditional Chinese medicine for over 2,000 years. With agricultural development, the harm of soft rot to P. ternata is an increasing problem. The lack of germplasm resources resistant to soft rot leads to less research on resistance mechanisms. In our study, we screened disease-resistant P. ternata P-1 and disease-susceptible P. ternata P-4 for the first time. Then, the infection of soft rot for 0, 24, and 48 hours was performed, and a de novo transcriptome analysis explored key genes associated with soft rot resistance. A total of 260,169 unigenes were identified and differentially expressed gene analysis was conducted. In total, 33 C3H-type ZFP genes were differentially expressed under Pectobacterium carotovorum infection. Transient expression of ZFP2-like (Cluster-5189.85444) resulted in a twofold increase at 24 hour post infection (hpi) and a threefold increase at 48 hpi in P-1 with soft rot infection, but no significant difference at P-4 enhanced the resistance of Nicotiana benthamiana to soft rot. Stable overexpression in P. ternata with a 2 ~ 11-fold increase in gene expression and reduced the lesion size from 6 mm to 2 ~ 4 mm at 24 hpi, demonstrating increased resistance to P. carotovorum. These findings indicated the ZFP2-like gene plays a pivotal role in soft rot resistance, enriches genetic data on disease resistance in P. ternata, and contributes to breed selection and improvement.