The herb-pair, Astragali Radix (AR) and Curcumae Rhizoma (CR), often occurs in traditional herbal prescriptions used for cancer treatment in Asian areas. In clinical application, the AR-CR herb pair was often produced by different preparation methods or with raw materials from different sources, which raised a challenge for quality control of the herb-pair medicines. In this paper, ultra high performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry method (UPLC-QQQ-MS) was applied for the first time to simultaneously determine 17 main bioactive components for quality control of AR-CR herb pair. The chromatographic separation was studied on an ACQUITY UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 μm) with a mobile phase composed of 0.1% aqueous formic acid and acetonitrile using a gradient elution in 12 min. The proposed method was optimized and validated by good linearity (r2 >0.9970), limit of detection (0.33–10.78 ng/mL), limit of quantification (0.81–2.54 ng/mL), intra- and inter-day precisions (RSD ≤ 3.64%, RSD ≤ 5.68%), stability (RSD ≤ 4.29%), repeatability (RSD ≤ 5.98%), recovery (90.20–107.60%). The established method was successfully applied to comparative analysis of main bioactive components in AR-CR herb pair and its single herbs, and quality evaluation of different batches of clinical dispensing granules. Compared to the single herb, the content of most liposoluble constituents such as curcumenol, curdione, isocurcumenol, furanodienone, curcumol, and germacrone were remarkable increased in their herb pair, suggesting mixed preparation produced synergistic effects on promoting the extraction of bioactive ingredients. This study is the first time to report the rapid and simultaneous analysis of 17 compounds in AR-CR herb pair by UPLC-QQQ-MS, and provides a feasible method for holistic quality control of preparations containing AR-CR herb-pair.