Egypt is the world's largest date producing country. Different functional foods pertaining to date seeds were attempted before. Phenolic phytochemicals are not well absorbed in gastrointestinal tract, which results in lower bioactivity. Nanotechnology helps to resolve poor oral bioavailability. Aim was to evaluate the in-vivo anti-inflammatory properties of date seed powder (DSP) nanoparticles (NPs) and infusion in rats fed a high fat diet (HFD). Twenty five Wistar rats were distributed among five groups; I (control), II (on HFD), III (on HFD and DSPNP1 1:5), IV (on HFD and DSPNP2 2:3), and V (on HFD and DSP infusion 1g/kg/day). Blood samples were tested for C-reactive protein (CRP), Serum amyloid-A (SAA), total cholesterol, HDL, albumin, creatinine, and some primary biochemical parameters. HFD induced significant elevations in cholesterol and inflammatory markers as compared to the controls; while, HDL, ALT, AST, creatinine and albumin showed no change in all rats. In all DSP treatment groups, total cholesterol levels were reduced significantly. Both DSP NPs and infusion caused significant decrease in CRP and SAA levels. DSP NPs exhibited the same anti-inflammatory effects as their free counterparts. Using polyvinyl alcohol NPs of DSP in a wt/wt ratio of 2 PVA: 3 DSP; resulted in an acceptable particle size and physicochemical properties.