The aim of the study was to develop 5-FU loaded pH and thermo-sensitive nanogels, capable of sensing change in tumour environment pH and triggering drug release at physiological temperature. Poly( N -isopropylacrylamide- co -acrylic acid) (PNA) nanogels (Ng's) were prepared via free radical polymerization. The prepared nanogels were screened for FT-IR, 1 H NMR, pH dependent lower critical solution temperature (LCST), and DLS. Selected Ng's were loaded with 5-FU and screened for FTIR, particle size, TEM, % EE, in vitro drug release, % hemolysis, pH dependent cytotoxicity, in vivo kinetics on Wistar rats, in vivo anti-cancer efficacy and mean life span on Swiss albino mice. FTIR and 1 H NMR confirmed the formation of PNA. The prepared nanogels exhibited pH dependent LCST. The particle size of selected PNA and 5-FU–PNA Ng's were found to be 70.25 and 131.5 nm respectively at 25 °C. Drug release from 5-FU–PNA Ng's was found to be extended and highly sustained at pH 5.5, 6.8 and 7.4. However, when compared with respect to individual pH, drug release in pH 7.4 PBS was quite minimal when compared to pH 5.5 and 6.8. The cytotoxicity of 5-FU–PNA Ng's increased with decrease in pH value. Additionally they could extend in vivo circulation time and displayed effective anti-cancer efficacy when compared to 5-FU injection for the same. Our results documented enhanced anti-cancer efficacy and mean life span in EAC bearing mice.