Liver cancer is one of the factors that threaten human life. Highly up-regulated in liver cancer (HULC), a kind of long non-coding RNA (lncRNA), is regarded as a favorable noninvasive biomarker for the early diagnosis of hepatocellular carcinoma (HCC). So a strategy focused on improving the sensitivity of HULC detection is urgently desired. In this work, a highly sensitive electrochemiluminescent (ECL) sensor was constructed using Au@Ag core-shell nanoparticles/graphene quantum dots (Au@Ag/GQDs) as a signal indicator to detect HULC. Compared with the individual gold or silver nanoparticles, Au@Ag core-shell nanoparticles exhibited large specific surface area, better catalysis and excellent electronic transmission capacity due to the synergistic effect between Au and Ag. Thus, the ECL performance of GQDs could be greatly promoted by Au@Ag core-shell nanoparticles. Under the optimal conditions, this proposed ECL sensor exhibited ultrahigh sensitivity for quantitative detection of HULC with a wide linear range from 1 fM to 5 nM and a low detection limit of 0.3 fM (S/N = 3). These results showed that the sensor was promising for the sensitive detection of lncRNA in clinical application.