Saposhnikovia divaricata (SD) is a traditional Chinese medicine (TCM) which has been commonly used for the treatment of rheumatoid arthritis (RA). However, its active components and mechanism of anti-RA are still unclear. Targeting rheumatoid arthritis-fibroblastoid synovial (RA-FLS) and synovial macrophages are promising strategies for RA treatment, and their membrane receptors are important targets for anti-RA active substances. A dual channel 3-mercaptopropyltrimethoxysilane (MPTS) modified 2D cell membrane chromatography (CMC) system was established to characterize dual-cell membrane binding active components in SD. Nine components retained on RAW-CMC column and 8 components retained on FLS-CMC column were screened out. Among them, 8 components retained well on both CMC columns. We further validate the pharmacological activity of 5-O-methylvisammioside, 3'-O-angeloylhamaudol, imperatorin, phellopterin and anomalin. They could efficiently target both inflammatory macrophages and fibroblast synovial cells, reduce the release of inflammatory factors, inhibit abnormal cell proliferation, and promote cell apoptosis. 5-O-methylvisammioside, which exhibited the best pharmacological ability on both target cells, inhibited the NF-κB pathway. Our results showed that the dual channel MPTS modified 2D CMC system is a practical method for rapid screening the active components in TCM binding on multiple target cells' membrane protein of a disease. The method is very suitable for elucidating the mechanism of TCM with multiple-components and targets, and rapid screening of lead compounds.