Resistance to chemotherapy remains a significant challenge for the treatment of pancreatic cancer. In addition to conventional therapeutic strategies, photodynamic therapy (PDT) has emerged as a compelling alternative for pancreatic cancer as it synergizes with various chemotherapeutics such as irinotecan, and oxaliplatin. However, the exact mechanisms by which PDT overcomes oxaliplatin resistance remains elusive. In this study, we explore the hypothesis that PDT improves oxaliplatin efficacies via photochemical internalization, in which lysosome-borne verteporfin/benzoporphyrin derivative (BPD) facilitates the release of oxaliplatin from endolysosomes upon light exposure. Indeed, endocytosis inhibitors caused a significant 4-fold reduction of oxaliplatin efficiency in 2D cultures and 3D microtumor models, indicating the importance of endocytosis for its therapeutic efficacy. BPD-containing nanoliposomes colocalized non-exclusively within lysosomal vesicles and facilitated significantly increased oxaliplatin efficacy in PDAC microtumor cultures when combined with low-dose PDT. X-ray fluorescence microscopy revealed that low-dose PDT improved intracellular oxaliplatin retention, although cell-specific differences were observed. These findings were associated with cell-specific regulation of copper chelators and drug transporters involved in oxaliplatin detoxification. Nonetheless, in vivo studies on orthotopic PANC-1 tumors in mice demonstrated increased response rates and reduced tumor growth when PDT was combined with oxaliplatin. In conclusion, this study revealed that low-dose PDT can induce lysosomal release of oxaliplatin and suggests that photochemical internalization with PEGylated nanoliposomes is a promising approach to enhance the safety and efficacy of oxaliplatin for pancreatic cancer treatment.