Chronic liver disorders are a serious global health issue due to their widespread incidence. Nephropathy described the deterioration of kidney function. Safe drug delivery by nanoparticles is a rapidly developing field with promising applications in the treatment of a wide variety of diseases. The current study aimed to evaluate the use of propolis nanoparticles for managing carbon tetrachloride (CCl4)-induced hepato-nephropathy on rats. Seventy adult males Spargue Dawley rats were allocated into 7 equal groups 10 rats of each. Control, CCl4, CCl4 +Silymarin, CCl4 + propolis, CCl4+Nanopropolis, CCl4 +Silymarin +Propolis, CCl4 +Silymarin +Nanopropolis. Hepato-nephropathy was induced with oral administration of CCl4 dissolved in olive oil at dose of (1gm/kg) for 4 weeks. Silymarin, propolis and nanopropolis were orally administrated at a dose of (200mg/kg), (100 mg/kg) and (30 mg/kg) respectively for 4 weeks post hepato-nephropathy onset. Biochemical, molecular analysis, histological assessment of liver and kidney and serum oxidative stress were done. CCl4 caused a marked deterioration in biochemical, oxidative stress markers (MDA, TAC, CAT), serum TNF-α, IgM, molecular markers (SMAD-2, SMAD-3, SMAD-7, MMP-9, Desmin, TGF-β1, and let-7b), and the histopathological pictures of both liver and kidney. The above-mentioned parameters were restored with administration of silymarim + Nano-propolis, silymarin + propolis, silymarin, Nano-propolis, and propolis in order. Based on the previous findings we could speculated that combined therapy of nano-propolis and silymarin could be implicated in managing hepato-nepheropathy since it improves both liver and kideny function by targeting let-7b/TGF-β/Smad Pathway.