In this work, a simple analytical strategy combining high-performance liquid chromatography–diode array detection (HPLC-DAD) and the chemometric method was developed for the simultaneous quantification of 5-hydroxymethyl-2-furfural (HMF), paeoniflorin (PAE), ferulic acid (FER), baicalin (BAI), and berberine (BER) in a Chinese medicine formula Wen-Qing-Yin (WQY). The alternating trilinear decomposition (ATLD) algorithm and alternating trilinear decomposition assisted multivariate curve resolution (ATLD-MCR) algorithm were used to realize the separation and rapid determination of five target analytes under the presence of time shifts, solvent peaks, peak overlaps, and unknown interferences. All analytes were eluted within 10 min and the linear correlation coefficients of calibration sets were between 0.9969 and 0.9996. In addition, the average recoveries of the five active compounds obtained by ATLD and ATLD-MCR analysis were in the range of 91.8–112.5% and 88.6–101.6%, respectively. For investigating the accuracy and reliability of the proposed method, figures of merit including limit of detection (LOD), limit of quantitation (LOQ), sensitivity (SEN), and selectivity (SEL) were calculated. The proposed analytical strategy has the advantages of being fast, simple, and sensitive, and can be used for the qualitative and quantitative analysis of WQY, providing a feasible option for the quality monitoring of the traditional Chinese medicine formula.