Introduction: Early identification of arterial injury by non-invasive imaging can facilitate research into mechanisms of arterial injury and has the potential to improve patient management. We tested the hypothesis that Lagrangian carotid strain imaging (LCSI) combined with adaptive Bayesian regularization could detect early arterial injury and monitor atherogenesis in a murine model by associating findings with histological examinations. Methods: Radio-frequency (RF) data were collected from the right and left common carotid arteries (CCA) of 10 (5 male and 5 female) ApoE tm1Unc/J mice at 6, 16 and 24 weeks using a high frequency ultrasound system. Cumulative axial, lateral and shear strain images were estimated using LCSI and 3 strain indices: maximum accumulated strain index (MASI), peak mean strain of full ROI index (PMSRI) and strain at peak axial displacement index (SPADI). Mice were euthanized (n=2 at 6 and 16 weeks, n=6 at 24 weeks) for histological examination. Results: We observed sex-specific differences in the temporal variation of strain indices. For male mice, axial PMSRI and SPADI changed significantly from 6 to 24 weeks (mean axial SPADI at 6 = 14.10±6.30 % and 24 weeks = 0.24±6.22%; p=0.0004). For female mice, lateral MASI was significantly higher at 24 than 6 weeks (mean lateral MASI at 6 = 10.26±3.13 % and 24 weeks = 16.42±7.15% p=0.048). Both sexes had strong associations with histological findings. For males, axial PMSRI and SPADI showed significant correlation with the number of elastin fibers (axial PMSRI: r s =0.83, p=0.01; axial SPADI: r s =0.76, p=0.02). For females, lateral and shear MASI had significant correlations with plaque scores (lateral MASI: r s =0.66, p=0.04; shear MASI: r s 0.77, p =0.009). Conclusions: LCSI can quantify carotid arterial wall strain in a murine model non-invasively. Changes in strain were associated with changes in arterial wall microstructure after plaque formation.