A pH and temperature-responsive copolymer hydrogel based on poly(N-isopropylacrylamide-co-glycidyl methacrylate)-melamine (pNIPAm-co-pGMA-Mela) was developed for the delivery of both hydrophobic and hydrophilic drugs. The hydrogel was synthesized by copolymerizing glycidyl methacrylate (GMA) with N-isopropylacrylamide (NIPAm) and functionalizing the resulting copolymer with melamine units. The hydrogel was characterized using 1H NMR, FTIR, SEM, zeta potential, and particle size analysis. The hydrogel was tested for drug release behavior under different pH (7.4 and 4.0) and temperature (25 °C, 37 °C, and 45 °C) conditions, with ibuprofen (Ibu) and 5-fluorouracil (5-Fu) as model hydrophobic and hydrophilic drugs. The results showed that the hydrogel exhibited pH and temperature-responsive drug release, with about 100% of Ibu and 5-Fu released at pH 4.0/45 °C. The hydrogel was also evaluated for in vitro biocompatibility and hemocompatibility using MDA-MB-231 cells, with the results indicating that the hydrogel is biocompatible and hemocompatible. The study suggests that the pNIPAm-co-pGMA-Mela hydrogel system is a promising drug delivery system for both hydrophilic and hydrophobic drug delivery applications.A pH and temperature-responsive copolymer hydrogel based on poly(N-isopropylacrylamide-co-glycidyl methacrylate)-melamine (pNIPAm-co-pGMA-Mela) was developed for the delivery of both hydrophobic and hydrophilic drugs. The hydrogel was synthesized by copolymerizing glycidyl methacrylate (GMA) with N-isopropylacrylamide (NIPAm) and functionalizing the resulting copolymer with melamine units. The hydrogel was characterized using 1H NMR, FTIR, SEM, zeta potential, and particle size analysis. The hydrogel was tested for drug release behavior under different pH (7.4 and 4.0) and temperature (25 °C, 37 °C, and 45 °C) conditions, with ibuprofen (Ibu) and 5-fluorouracil (5-Fu) as model hydrophobic and hydrophilic drugs. The results showed that the hydrogel exhibited pH and temperature-responsive drug release, with about 100% of Ibu and 5-Fu released at pH 4.0/45 °C. The hydrogel was also evaluated for in vitro biocompatibility and hemocompatibility using MDA-MB-231 cells, with the results indicating that the hydrogel is biocompatible and hemocompatible. The study suggests that the pNIPAm-co-pGMA-Mela hydrogel system is a promising drug delivery system for both hydrophilic and hydrophobic drug delivery applications.