Background: Numerous studies have indicated that IQGAP1 plays an important role in human cancers. The present study aimed to investigate the IQGAP1 expression pattern in papillary thyroid cancer (PTC) and its relationship with tumor proliferation, invasion and metastasis. Methods: Fresh samples from PTC patients were assessed for the expression levels of IQGAP1 by qPCR, western blotting and immunochemistry assays. Mechanistically, genetic knockdown with siRNA was used to study IQGAP1 protein function. We also examined in vitro cell growth by MTT assay and soft-agar colony formation assays, and cell proliferative index (PI) and apoptosis by flow cytometry analysis. Additionally, cell migration/invasion ability was investigated by Transwell and scratch assays. The potential regulatory mechanisms of IQGAP1 in PTC were further explored by bioinformatics. Results: We found that IQGAP1 mRNA and protein expression levels in primary tumor tissue were significantly higher than in para-tumor and normal thyroid tissues. Metastatic lymph nodules had the highest expression level of IQGAP1. Compared with blank and negative control cells, silencing the Iqgap1 gene with siRNA in K1 and TPC-1 cells inhibited their proliferation and cellular invasion/migration abilities significantly. The bioinformatics analysis revealed that upregulated IQGAP1 expression was related to a series of important pathways and mechanisms involved in tumorigenesis and progression. Conclusions: IQGAP1 may play an important role in tumorigenesis, invasion and metastasis in PTC; furthermore, it may serve as a biomarker for the diagnosis of malignant PTC, and the targeting of this novel molecular marker may have potential therapeutic benefit in PTC.