Although pancreatic ductal adenocarcinoma (PDAC) is associated with limited treatment options and poor patient outcomes, targeted α-particle therapy (TAT) represents a promising development in the field. TAT shows potential in treating metastatic cancers, including those that have become resistant to conventional treatments. Among the most auspicious radionuclides stands the in vivo α-generator ²¹²Pb. Combined with the imaging-compatible radionuclide ²⁰³Pb, this theranostic match is a promising modality rapidly translating into the clinic. Using the pretargeting approach between a radiolabeled 1,2,4,5-tetrazine (Tz) tracer and a trans-cyclooctene (TCO) modified antibody, imaging and therapy with radiolead were performed on a PDAC tumor xenograft mouse model. For therapy, 3 cohorts received a single administration of 1.1, 2.2, or 3.7 MBq of the pretargeting agent, [²¹²Pb]Pb-DO3A-PEG₇-Tz, whereby administered activity levels were guided by dosimetric analysis. The treated mice were holistically evaluated; minimal-to-mild renal tubular necrosis was observed. At the same time, median survival doubled for the highest-dose cohort (10.7 wk) compared with the control cohort (5.1 wk). This foundational study demonstrated the feasibility and safety of pretargeted TAT with ²¹²Pb in PDAC while considering dose limitations and potential adverse effects.