Papaya is a valuable crop that is widely cultivated, but it is vulnerable to Erwinia mallotivora, the pathogen that causes papaya dieback disease (PDD). Although effector and pathogenesis related genes have been identified, little is known about potential resistance genes and pathways involved in the PDD. A dual RNA sequencing (RNA-Seq) provided insights into host resistance or susceptibility to PDD and its pathogenesis. Host-pathogen interactions were evaluated in the Carica papaya varieties Eksotika (susceptible) and Viorica (highly tolerant) pre-inoculation, and at 6, 24, and 48-h post inoculation (HPI) with E. mallotivora using dual RNA-seq analysis. Comparative analysis between the three treatments in the host using DESeq2 revealed 420, 89, and 378 significantly differentially expressed genes (DEGs) at 6, 24 and 48 (HPIs), respectively. A total of 61 DEGs were identified in E. mallotivora at 6 HPI while 429 were identified at 48 HPI. Six putative effectors were found to be highly expressed at 48 HPI, indicating their involvement during late infection. In addition, three putative resistance gene families were highly expressed at 48 HPI, indicating their possible involvement in the resistance and defence mechanisms. The co-expression network analysis of effector (T3SS) genes and transcription factors related to the biotic stress response revealed an interaction between them, suggesting their involvement in the defence mechanism. The KEGG pathway enrichment analysis of DEGs in C. papaya suggests that the diterpenoid biosynthesis pathway and photosynthesis are correlated with defence strategies. The dual RNA-seq analysis enables the identification of candidate genes associated with the pathogenesis mechanism of E. mallotivora thus shedding some light on the discovery events in the stages of bacterial infection of C. papaya by E. mallotivora.