Costello Syndrome (CS) is a distinctive rare multisystem disorder comprising characteristic prenatally increased growth retardation, coarse facial features, redundant skin with deep palmar, plantar creases and papillomata of later onset. CS patients present also laxity of small joints, tight Achilles tendons, cardiac malformations, and developmental delay. The primary cause of CS was associated to the germ line activation of HRAS oncogene, with a common missense mutation G12S in 80% of the patients. Here we describe the generation and the consequent phenotypic characterization of a genetically engineered mouse model of CS, by introducing the oncogenic G12S mutation by homologous recombination into the mouse Hras gene, Hrastm1.1Ics. The effect of the HRAS G12S mutation was evaluated on behavioral, visual, metabolic, cardiac and histological traits in young adult animals. The behavioral analysis revealed that HRASG12S mutant males displayed reduced locomotor activity, accompanied by decreased muscle strength and altered motor coordination performance. In addition, the cardiac exploration revealed that HRASG12S mutants exhibit a hypertensive phenotype combined with tachycardia. In conclusion, the HRASG12S mutant mice showed a polysyndromic phenotype reproducing some of the CS features observed in patients. The future study of the here-described CS mouse model should have a significant impact of our understanding of CS disease. The use of HRASG12S mutant mice as a CS mouse model opens up new fields of investigation to better understand the pathophysiology of the disease and to evaluate drugs dedicated to the reduction of the disease associated symptoms.