Papillary thyroid carcinoma (PTC) is one of the most common cancers of the endocrine system. Previous studies have shown that the extract of hull-less pumpkin seed (HLPS) has a significant anti-cancer effect. The aim of this study was to evaluate the effect of this plant extract on the proliferation of PTC cells. In this study, an extract of this plant was prepared by soxhlet extraction method and analyzed by Gas Chromatography-Mass Spectrometry. The cytotoxicity of PTX and plant extract was investigated using the methylthiazol tetrazolium (MTT) method. For careful investigation of morphological alteration, we used hematoxylin and eosin and Giemsa stinging. Based on MTT assay test, the IC50 value of paclitaxel (PTX) was significantly less than the hydro-alcoholic extract of HLPS at all of the incubation time. Our results of histological staining showed that HLPS and PTX induced significant morphological alteration in the PTC cultured cell that consistent with cell death. Comparing the groups treated by PTX or HLPS with control group showed significant differences. It seems that HLPS extract has an apparent effect on treatment of PTC, at least in laboratory condition, albeit for realistic decision about the effect of HLPS on PTC, more molecular investigations are necessary.