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_sKO) mice] rapidly impairs thyrocyte function and leads to hypothyroidism. Consequently, iTGa_sKO mice show reduced food intake and activity. However, body weight and the amount of white adipose tissue were decreased only in male iTGα_sKO 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_sKO 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/GFASEB J. 32, 6239–6251 (2018). www.fasebj.org