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Gemcitabine (GEM), as a first‐line chemotherapeutics for pancreatic ductal adenocarcinoma (PDAC) treatment, still faces several clinical challenges, restricted by instability in blood circulations, low tumor selectivity, and acquired nature characteristics of chemo‐resistance. To solve these challenges, the rational design of combination therapy with GEM and other therapy modalities is imperative. Herein, a small molecular self‐assembly nano‐prodrug is developed, which can achieve the co‐delivery of GEM, Ferrocene and nutlin‐3a on the achievement of GEM‐induced apoptosis with ferroptosis. In this nano‐prodrug, the disulfide linkage not only acts as a GSH‐responsive trigger but also plays an important role in self‐assembly behavior of nanoparticle that can load nutlin‐3a. Interestingly, nutlin‐3a plays an important role in both ferroptosis and apoptosis, one is effectively sensitized cells to ferroptosis by inhibiting cystine uptake, and the other is promoted apoptosis by elevating p53 expression. To further enhance the drug tumor accumulation and maintain stability in systemic circulations, this nano‐prodrug is then encapsulated into plectin1 receptor‐targeting phospholipid micelles (DSPE‐PEG‐PTP), which displays high selective tumor inhibition and good biosafety on different mice models, especially in orthotopic and patient‐derived xenograft (PDX) models. The findings provide new insights into the combination therapy of GEM with ferroptosis for reduced chemo‐resistance on PDAC treatment. [ABSTRACT FROM AUTHOR]