Introduction The La ribonucleoprotein 6 (LARP6), an RNA binding protein, increases type I collagen expression by regulating mRNA stability and translation. This is mediated via its interaction with the 5’ stem loop (5’SL) structure in collagen I mRNA. Disrupting this interaction by mutating the 5’SL region has been shown to reduce fibrotic remodeling in liver. Therefore, we tested the hypothesis that this interaction plays a role in cardiac fibrosis and stiffening in diet induced obesity in 5’SL mutant and wild‐type littermate mice. In fact, obesity and hypertension promote remodeling and cardiac stiffening due to excess collagen deposition, fibrosis, and microvascular dysfunction, that ultimately lead to diastolic dysfunction. Methods Male and female 5’SL mice and wild‐type (WT) littermates were fed a high fat high sucrose (HFHS) or control diet starting at 6 weeks of age. After 28 weeks of feeding, mice were assessed for cardiac function by echocardiography. Hearts were collected and a transverse section of the left and right ventricle was fixed for histology. RNA was isolated from the left ventricle and submitted for mRNA sequencing and qPCR. Results Following 28 weeks of a HFHS diet, male and female mice showed increased body weight, cardiac hypertrophy (heart weight normalized to tibia length), and diastolic dysfunction. However, the 5’SL mutation attenuated the impaired diastolic function in male, but not female mice. Surprisingly, cardiac fibrosis was not altered by the HFHS diet. RNA sequencing revealed that HFHS diet altered gene expression associated with glucose and ketone metabolism, as well as inflammation, in male WT littermates. However, the 5’SL mutation enriched gene networks associated with vascular development and angiogenesis. Conclusions Chronic HFHS feeding leads to increased body weight, hypertrophic cardiomyopathy, and diastolic dysfunction in both male and female mice. However, the 5’SL mutation blunts dysfunction only in male mice, demonstrating sex‐dependent cardioprotective effects.