High-fat diets (HFDs) have become increasingly prevalent in modern societies, driving rising rates of obesity and metabolic syndrome. Concurrently, radiation exposure from medical treatments and environmental sources poses health risks shaped by both biological and environmental factors. This review explores the intersection between HFDs and radiation sensitivity/susceptibility, focusing on how diet-induced metabolic alterations influence the body's response to radiation. Evidence from preclinical and clinical studies indicates that HFDs significantly alter metabolism, leading to increased oxidative stress and immune system dysregulation. These metabolic changes can exacerbate radiation-induced oxidative stress, inflammation, and DNA damage, potentially increasing radiation sensitivity in normal tissues. Conversely, obesity and HFD-induced metabolic disruptions may activate cellular pathways involved in DNA repair, cell survival, and inflammatory responses, fostering tumor resistance and modifying the tumor microenvironment, which may impair the efficacy of radiation therapy in cancer treatment. Understanding the interplay between diet and radiation exposure is critical for optimizing public health guidelines and improving therapeutic outcomes. These findings underscore the need for further research into dietary interventions that may mitigate radiation-associated risks.