Chitosan-polyethylene glycol (CS-PEG)-modified long-circulating liposomes were developed and loaded with tanshinone I (TaI@CS-PEG-L) to overcome its poor solubility and low bioavailability, as well as enhance the lipid-lowering efficacy of atorvastatin (At) and mitigate its tissues toxicity. After synthesis of CS-PEG copolymer, it was characterized with infrared and proton nuclear magnetic resonance. Thin-film hydration was used to prepare TaI@CS-PEG-L before optimization was performed using Box-Behnken design. Optimal liposomal formulation was obtained when mass ratio of lecithin:cholesterol:TaI mass ratio was 12:1:1 along with 0.2% CS-PEG, which displayed appropriate particle size (117.41 nm), polydispersity index (0.182), zeta potential (+17.31 mV), encapsulation efficiency (93.15%), and drug loading (5.19%). Besides, the liposomal preparation exhibited good long-term storage stability (over 30 days at 4 °C and 25 °C) and satisfactory gastrointestinal stability in simulated gastric (pH 1.2) and intestinal (pH 6.8) fluids for 4 h. TaI@CS-PEG-L displayed increased cellular uptake and in vitro release compared with free TaI and unmodified liposomes. Regarding pharmacokinetic studies, TaI@CS-PEG-L increased AUCₜ, t/, and C in rats by 7.26-fold, 2.43-fold, and 3.12-fold, respectively, which indicates significantly enhanced oral bioavailability. TaI@CS-PEG-L monotherapy markedly lowered serum lipid levels in hyperlipidemic mice, thereby improving liver function indices, and alleviating pathological liver injury. TaI@CS-PEG-L demonstrated synergistic lipid-lowering effects and efficiently reversed At-induced hepatic and pancreatic injuries after combination with At, thus outperforming free TaI and TaI@L. Therefore, CS-PEG-modified long-circulating liposomes could efficiently address delivery challenges of TaI, thereby yielding a formulation that could potently lower serum lipid levels and protect liver against injury. The findings of this study offer a promising 'efficacy-enhancing and toxicity-reducing' strategy for potential treatment of hyperlipidemia in the clinics.