An analytical method was established using high-performance liquid chromatography coupled with diode array and evaporative light scattering detectors (HPLC-DAD-ELSD) with -C18 and -NH2 column tandem for the simultaneous determination of hydrophobic atractylenolide I, II, III, atractylone and hydrophilic compounds glucose, fructose and sucrose in the dried rhizome of Atractylodes macrocephala Koidz (a natural raw material for health foods, Bai-Zhu aka. in Chinese). The method combines the different separation capabilities of reversed-phase liquid chromatography and hydrophilic interaction liquid chromatography. It can provides a new choice for the simultaneous determination of hydrophilic and hydrophobic compounds in traditional Chinese medicines and health foods. It provided a reference method for the quality control of Bai-Zhu. The results showed that the linear correlation coefficients of the established column tandem chromatographic method were all greater than 0.9990, the relative standard deviation was 0.1–2.8%, and the average recovery was 96.7–103.1%. The contents of atractylenolide I, II, III, atractylone, fructose, glucose, and sucrose in 17 batches of Baizhu were 172.3–759.8 μg/g, 201.4–612.8 μg/g, 160.3–534.2 μg/g, 541.4–8723.1 μg/g, 6.9–89.7 mg/g, 0.7–7.9 mg/g, and 1.2–21.0 mg/g, respectively.