Myocardial infarction (MI) is the leading cause of morbidity and mortality worldwide. Nanoparticle systems carrying drugs have already been developed to treat MI. To improve the efficiency of tanshinone (TAN), and to achieve the synergistic effect of TAN and puerarin (PUE), PUE-prodrug and TAN co-loaded solid lipid nanoparticles (SLN) was structured and utilized for MI treatment in the present research. PUE-prodrug was synthesized by an esterification reaction. PUE-prodrug and TAN co-loaded SLN (PUEp/TAN-SLN) were prepared by a single emulsification followed by a solvent evaporation method. The physicochemical properties of SLN were characterized and the in vivo infarct therapy effects were evaluated in MI rats. PUE-prodrug and TAN contained SLN showed a size of 112.6 ± 3.1 nm. The SLN encapsulation reduced the cytotoxicity of drugs and was a safer system. PUEp-SLN exhibited a 1.7-fold increase in comparison to PUE-SLN (21.2 ± 2.1 versus 12.5 ± 1.5 mg/L), in the mean time a 3.4-fold increase compared with free PUE in heart drug concentration (21.2 ± 2.1 versus 6.3 ± 0.9 mg/L). In vivo infarct therapy efficiency of double drugs loaded PUEp/TAN-SLN (17 ± 1.9%) was significantly better than the single drug loaded PUEp-SLN (31 ± 1.6%) and TAN-SLN (40 ± 2.2%). PUE-prodrug contained, double drugs co-loaded SLN can be utilized as promising candidate delivery system for cardioprotective drugs in treatment of myocardial infarction.