Simple Summary: Pancreatic cancer (PC) is related to lifestyle risks, chronic inflammation, and germline mutations. Surgical resection and adjuvant chemotherapy are the main therapeutic strategies but are less effective in patients with high-grade tumors. Oxygen-ozone (O2/O3) therapy is an emerging alternative tool for the treatment of several clinical disorders. The advantages of using cannabinoids have been evaluated in several human cancers. Regarding PC, activation of cannabinoid receptors was found to induce PC cell apoptosis without affecting the normal pancreas cells. Herein, we evaluate the anticancer effect of cannabidiol (CBD) and O2/O3, alone or in combination, on two human pancreatic ductal adenocarcinoma (PDAC) cell lines, PANC-1 and MiaPaCa-2, examining expression profiles of 92 pancreatic adenocarcinoma associated genes, cytotoxicity, migration properties, and cell death. Finally, we assess the combination effects with gemcitabine and paclitaxel. Summarizing, for the first time the antitumoral effect of combined therapy with CBD and oxygen-ozone therapy in PDAC is evidenced.