DOXC is one of the 2-oxoglutarate-dependent dioxygenases (2OGDs) classes, which is involved in the biosynthesis of colorful flavonoids and plant hormones. Safflower (Carthamus tinctorius L.) is a commonly used plant with flavonoids. Herein, we focused on analyzing the characterization, transcript abundance, and correlation of DOXC-class 2OGDs in safflower with flavonoids for the first time. TBLASTN analysis showed that they were implicated in the biosynthetic pathway of ethylene (DOXC1 and DOXC2), indole-3-acetic acid (DOXC3, DOXC4, and DOXC5), flavonoids (DOXC6, DOXC7, and DOXC8), and scopolamine (DOXC9 and DOXC10). The transcript abundance of DOXC1, DOXC2, DOXC6, DOXC7, and DOXC10 response to methyl jasmonate (MeJA) in two safflower lines (orange-yellow-flowered safflower line with major quinochalcones and minor flavonols, white-flowered safflower line with major flavonols and without quinochalcones) had converse transcript level accumulation. Coexpression analyses displayed that the transcript level of DOXC1, DOXC2 and DOXC8 was positively correlated with hydroxysafflor yellow A, a major quinochalcone in orange-yellow-flowered safflower line. DOXC3, DOXC4, DOXC5, DOXC7, and DOXC9 displayed a marked positive correlation with kaempferol-3-O-β-D-glucoside, a main flavonols in white-flowered safflower line. The response models of DOXC3, DOXC4, DOXC5 and DOXC9 showed amazing similarity in different safflower line, but the correlations with flavonoids were actually quite distinct. In orange-yellow-flowered safflower line, they might be implicated in the rutinoside modification of kaempferol and quercetin, but their functions were different and diversity in white-flowered safflower line. In sum, ten DOXC-class 2OGDs from safflower displayed different sequence features. Simultaneously, their expression pattern in two safflower lines in response to MeJA treatment, as well as their correlation with flavonoids, was different. These results implied the diversification of DOXC-class 2OGDs is partly responsible for the diversity and complexity of specialized metabolites in different phenotypes and chemotypes of safflower lines.