ABSTRACT Thyroid function is controlled by thyroid‐stimulating hormone (TSH), which binds to its G protein‐coupled receptor [thyroid‐stimulating hormone receptor (TSHR)] on thyrocytes. TSHR can potentially couple to all G protein families, but it mainly activates the G s ‐ and G q/11 ‐mediated signaling cascades. To date, there is a knowledge gap concerning the role of the individual G protein cascades in thyroid pathophysiology. Here, we demonstrate that the thyrocyte‐specific deletion of G s protein α subunit (Gαs) in adult mice [tamoxifen‐inducible G s protein a subunit deficient (iTGα s KO) mice] rapidly impairs thyrocyte function and leads to hypothyroidism. Consequently, iTGa s KO mice show reduced food intake and activity. However, body weight and the amount of white adipose tissue were decreased only in male iTGα s KO mice. Unexpectedly, hyperplastic follicles and papillary thyroid cancer‐like tumor lesions with increased proliferation and slightly increased phospho‐ERK1/2 staining were found in iTGα s KO mice at an older age. These tumors developed from nonrecombined thyrocytes still expressing Gα s in the presence of highly elevated serum TSH. In summary, we report that partial thyrocyte‐specific Gα s deletion leads to hypothyroidism but also to tumor development in thyrocytes with remaining Gα s expression. Thus, these mice are a novel model to elucidate the patho physiological consequences of hypothyroidism and TSHR/G</cAMP‐mediated tumorigenesis.—Patyra, K., Jaeschke, H., Löf, C., Jännäri, M., Ruohonen, S. T., Undeutsch, H., Khalil, M., Kero, A., Poutanen, M., Toppari, J., Chen, M., Weinstein, L. S., Paschke, R., Kero, J. Partial thyrocyte‐specific Gas deficiency leads to rapid‐onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma‐like lesions in mice. FASEB J. 32, 6239–6251 (2018). www.fasebj.org