The objective of the current research study was to formulate the PEGylated lipid polymer hybrid nanoparticles of ergotamine and caffeine for intranasal administration with higher entrapment efficiency, better permeability, desirable controlled release pattern, and significant brain uptake in animal studies. A single-step nanoprecipitation method was employed in the processing of self-assembled hybrid nanoparticles constituting polymer PLGA, lipids soya lecithin, and DPPC with PEGylation using polyethylene glycol (PEG-2000). The optimal lipid/polymer weight ratio of 15% w/w showed lower particle size of 239.46 ± 2.31 nm with good colloidal stability depicted by zeta potential (− 18.36 ± 6.59 mV), higher entrapment efficiency of 86.88 ± 1.67%, and controlled release profile when evaluated for in vitro and ex vivo studies as 97.12 ± 2.79% and 75.13 ± 5.62% release, respectively, for 48 h. The formulation showed long-term serum stability when incubated in bovine serum albumin and displayed high brain uptake (4.35-fold) offering significant permeability in the brain post-intranasal administration via olfactory route. Histopathological investigations and serotonin toxicity studies in animals confirmed the safe and non-toxic nature of the formulation while the acetic acid writhing test proved the anti-hyperalgesic activity. The PEGylated lipid polymer hybrid nanoparticles of ergotamine and caffeine showed synergistic activity with efficacious higher anti-migraine potential.