Non-long terminal repeat (Non-LTR) retrotransposons are mobile genetic elements that replicate through a “copy-and-paste” mechanism, enabling their expansion within the genome. Aberrant activation of these elements can induce genomic instability, elicit cellular stress responses, and activate inflammasome signaling, leading to tissue injury and disease. The central process of sterile inflammation involves the release and recognition of damage-associated molecular patterns (DAMPs), endogenous molecules that initiate inflammatory responses and form a common basis for many sterile inflammatory disorders. Recent studies have identified non-LTR retrotransposons as key endogenous triggers of DAMP-like signaling that drive sterile inflammation in both neuronal and non-neuronal tissues, contributing to the development of neurodegenerative and other chronic inflammatory diseases. In this review, we summarize recent advances in understanding how non-LTR retrotransposons, particularly LINE and SINE elements, influence sterile inflammation and disease pathogenesis. We highlight how their mobilization reshapes genomic architecture and gene regulation, and how the resulting signaling cascades promote chronic inflammation, immune dysregulation, and tissue injury. We also discuss emerging therapeutic strategies aimed at suppressing retrotransposon activity or interrupting downstream inflammatory signaling for treating sterile inflammation-related diseases.