Periostin is a multifunctional extracellular matrix protein involved in various inflammatory diseases and tumor metastasis; however, evidence regarding whether and how periostin actively contributes to inflammation-associated tumorigenesis remains elusive. Here, we demonstrate that periostin deficiency significantly inhibits the occurrence of colorectal cancer in azoxymethane/dextran sulfate sodium-treated mice and in ApcMin/+ mice. Moreover, periostin deficiency attenuates the severity of colitis and reduces the proliferation of tumor cells. Mechanistically, stromal fibroblast-derived periostin activates FAK-Src kinases through integrin-mediated outside-in signaling, which results in the activation of YAP/TAZ and, subsequently, IL-6 expression in tumor cells. Conversely, IL-6 induces periostin expression in fibroblasts by activating STAT3, which ultimately facilitates colorectal tumor development. These findings provide the evidence that periostin promotes colorectal tumorigenesis, and identify periostin- and IL-6-mediated tumor-stroma interaction as a promising target for treating colitis-associated colorectal cancer. Display omitted •Periostin deficiency inhibits colorectal tumor formation in mice•Periostin is mainly secreted by fibroblasts to promote tumor cell proliferation•Periostin promotes YAP/TAZ nuclear localization and IL-6 expression in tumor cells•IL-6 promotes fibroblast activation and periostin expression during tumorigenesis Ma et al. demonstrate that fibroblast-derived periostin promotes colorectal tumorigenesis by enhancing YAP/TAZ nuclear localization and IL-6 expression in tumor cells. Conversely, IL-6 promotes periostin expression in fibroblasts via STAT3 signaling. This work identifies crosstalk between stromal cells and tumor cells via periostin and IL-6 during colorectal tumorigenesis.