Colorectal cancer (CRC) is a cancer-associated fibroblast, CAF-rich tumor. CAF promotes cancer cell proliferation, metastasis, drug resistance via secretes soluble factors, and extracellular matrices which leads to dense stroma, a major barrier for drug delivery. Resveratrol (RES) is a polyphenolic compound, has several pharmacologic functions including anti-inflammation and anticancer effects. Considering tumor microenvironment of CRC, resveratrol-loaded liposome (L-RES) was synthesized and employed to inhibit CAF functions. The L-RES was synthesized by thin-film hydration method. The cytotoxicity of L-RES was evaluated using MTT assay. Effect of L-RES treated CAF on tumor spheroid growth was performed. Cell invasion was determined using spheroid invasion assay. The effect of L-RES on 5-fluorouracil (5-FU) sensitivity of CRC cells was determined in co-cultured tumor spheroids. Subtoxic dose of L-RES was selected to study possible inhibiting CAF functions. Decreased CAF markers, α-SMA and IL-6 levels, were observed in L-RES treated activated fibroblast. Interestingly, the activated fibroblast promoted invasive ability and drug resistance of CRC cells in co-culture condition of both 2D and 3D cultures and was attenuated by L-RES treatment in the activated fibroblast. Therefore, L-RES provides a promising drug delivery strategy for CRC treatment by disrupting the crosstalk between CRC cells and CAF.