This study presents nanostructured lipid carrier (NLC) co-loaded with Docetaxel (DCT) and 5-Fluorouracil (5-FU) as a targeted therapeutic approach for gastric cancer (GC). Using nanoprecipitation, NLC-DCT/5-FU were synthesized and exhibited an average particle size of 215.3 ± 10.4 nm, a polydispersity index (PDI) of 0.29, and a zeta potential of - 17.1 mV. Encapsulation efficiency reached 95.9% for DCT and 5-FU, with a loading efficiency of 11.2%. In vitro release studies demonstrated a biphasic release profile, with an initial burst and sustained release, achieving 85.6% DCT and 75.8% 5-FU release over 72 h. Cytotoxicity assays in MKN45 cells showed a significantly lower half-maximal inhibitory concentration (IC) for NLC-DCT/5-FU (0.3 µM) compared to free DCT (3.9 µM) and free 5-FU (19.5 µM), indicating enhanced efficacy. In vivo evaluation in a GC mouse model confirmed substantial tumor volume reduction to 213 mm with NLC-DCT/5-FU treatment, compared to 432 mm with the free-drug combination. Systemic safety assessment showed minimal adverse effects, suggesting the nanoparticles' enhanced therapeutic index. These results demonstrate that NLC-based co-delivery systems could substantially improve the clinical outcomes of GC therapy.