Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate below 5%. CA19-9 is the most commonly used blood-based biomarker for PDAC in current clinical practice, despite having been shown repeatedly to be inaccurate and have poor diagnostic performance. This review aims to assess the reported diagnostic accuracy of all blood-based biomarkers investigated to date in PDAC, by directly comparing individual biomarkers and multi-biomarker panels, both containing CA19-9 and not (novel). A systematic review was conducted in accordance with PRISMA standards in July 2020. Individualised search strategies for three academic databases identified 5,885 studies between the years 1973-2020. After two rounds of screening, 250 studies were included. Data were extracted and assessed for bias. A multivariate three-level meta-analysis with subgroup moderators was run in R using AUC values as effect size. Based on this model, the pooled AUC value for all multi-biomarker panels (AUC=0.898, 95% CI:0.88-0.91) was significantly higher than all single biomarkers (AUC=0.803, 95% CI:0.78-0.83)(p<0.0001). The pooled AUC value for CA19-9 alone was significantly lower compared to the multi-biomarker panels containing CA19-9 (p<0.0001). For the novel biomarkers, the pooled AUC for single biomarkers was also significantly lower compared to multi-biomarker panels (p<0.0001). Novel biomarkers that have been repeatedly examined across the literature, such as TIMP-1, CEA and CA125, are highlighted as promising. These results suggest that CA19-9 may be best used as an addition to a panel of biomarkers rather than alone, and that multi-biomarker panels generate the most robust results in blood-based PDAC diagnosis.