Non-small cell lung cancer (NSCLC) is among the leading global causes of cancer-related mortality. Current treatment options have limited efficacy and severe adverse effects, underlining the necessity for innovative therapeutic strategies. Among emerging strategies, NFκB inhibition is particularly promising, as NFκB is considered a master regulator of NSCLC pathogenesis. NFκB activity can be efficiently inhibited by double-stranded decoy oligodeoxynucleotides (ODNs). However, therapeutic use of ODNs is strongly limited by enzymatic degradation and poor transport across cell membranes. In this study, we report the encapsulation of a small hydrophilic NFκB decoy ODN into a biodegradable, biocompatible, and acid-responsive dextran-based nanoparticle (NP) system. This formulation has shown excellent encapsulation efficiency (up to 99.5%) with 185 nm average particle size and pH-dependent ODN release at acidic pH. NFκB decoy ODN NPs showed promising anticancer activity, with significant anti-proliferative, anti-migratory, and anti-colony formation activity. These were measured by MTT assay, Boyden chamber and scratch wound healing assays, and crystal violet staining, respectively. Mechanistically, the anti-proliferative effect was exerted through the activation of the expression of key genes regulating apoptosis and necroptosis such as TNF-α, RIPK1, RIPK3, and MLKL. The findings of this study provide the foundations for further investigation of the molecular mechanisms by which NFκB inhibition results in anticancer activity, simultaneously providing proof-of-concept of the therapeutic potential of dextran-based nanoparticles carrying NFκB decoy ODNs against NSCLC.