Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, largely because it is diagnosed late. Diagnosis typically relies on imaging and biopsy, but only after tumors have advanced, which reduces treatment effectiveness. Current biochemical biomarkers are limited to CA19-9, which is more useful for prognosis and monitoring than for diagnosis. Circulating miRNAs may offer minimally invasive complementary biomarkers for PDAC diagnosis, potentially accounting for ethnic and treatment-related variables. We performed small RNA sequencing on plasma from five non-metastatic-stage and five metastatic-stage PDAC patients and 10 healthy controls to generate an exploratory miRNA profile. Candidate miRNAs were then validated by RT-qPCR in an independent cohort of 70 PDAC patients and 106 healthy controls, and nine miRNAs showed promising differential plasma expression. Notably, miRNA484 and miRNA335-5p were associated with PDAC in CA19-9-negative patients, with ROC AUCs of 0.984 and 0.88, respectively. Overall, these results indicate that miRNA484 and miRNA335-5p may have clinical value as complementary biomarkers for PDAC patients who are CA19-9-negative.