Lower back pain is a leading cause of disability worldwide, and has been associated with intervertebral disc (IVD) degeneration. The causes of IVD degeneration are multifactorial, and diet, age, and diabetes have all been linked to IVD degeneration. Advanced glycation endproducts (AGEs) are known to accumulate in the IVD as a result of diet and diabetes, and AGE accumulation in the IVD has been shown to induce oxidative stress and catabolic activity that result in collagen damage. While an association between AGE accumulation and IVD degeneration is emerging, understanding the mechanism behind the association is unclear and the focus of these studies. Research has pointed to the role of the AGE receptors in AGEinduced degeneration, especially the Receptor for AGES (RAGE), which is thought to induce the catabolic response of the IVD to an AGE challenge. In other organ systems, the AGE receptor Galectin 3 (Gal3) has had a protective effect in AGE challenge. In this study, we have used an IVD organ culture model with genetically modified mice to analyze the role of RAGE and Gal3 in an AGE challenge. Gal3 was shown to be protective against an AGE challenge in the murine IVD ex vivo, protecting against molecular collagen damage and biomechanical property changes. Gal3 receptor levels in the AF significantly decreased upon an AGE challenge. RAGE presence was necessary for AGE-induced collagen damage in the IVD, and RAGE receptor levels in the AF significantly increased upon AGE challenge. These findings implicate Gal3 in the response of the IVD to an AGE challenge and shed greater understanding on the role of AGE receptors in AGE-induced IVD degeneration. This research can help guide future studies in understanding the mechanisms of AGE-induced IVD degeneration and look towards therapeutics and preventative care for IVD degeneration.