Hydroxysafflor yellow A (HSYA) is the main bioactive flavonoid extracted from the flower of Carthamus tinctorius L., which is widely used in traditional Chinese medicine for the treatment of myocardial ischemia and cerebral ischemia. HSYA has high water solubility but poor intestinal membrane permeability, resulting in low oral bioavailability. Currently, only HSYA sodium chloride injection has been approved for clinical use and oral formulations are urgently needed. In this study, HSYA solid lipid nanoparticles (SLNs) with the structure of w/o/w were prepared by a warm microemulsion process using approved drug excipients for oral delivery to increase the oral absorption of HSYA. The optimized HSYA SLNs are spherical with an average size of 214 nm and the encapsulation efficiency is 55%. HSYA SLNs exhibited little cytotoxicity in Caco-2 and Hela cells, but increased the oral absorption of HSYA about 3.97-fold in rats, compared to HSYA water solution. In addition, cycloheximide pretreatment significantly decreased the oral absorption of HSYA delivered by SLNs. Importantly, the pharmacodynamics evaluation demonstrated that SLNs further decreased the infarct areas in rats. In conclude, SLNs could be a promising delivery system to enhance the oral absorption and pharmacological activities of HSYA.