Cancerous cells guarantee their immortality by maintaining their telomere length and altering DNA damage response (DDR) pathways. Telomeres are repetitive nucleoprotein structures capping both ends of linear chromosomes, having progressive erosion over cell division. Most normal cells face senescence or apoptosis when telomere length reaches a certain length. However, cancerous cells bypass the cell division boundary by activating a ribonucleoprotein enzyme named telomerase or alternative lengthening of telomeres (ALT). Moreover, DDR protein regulation has a tight interaction with telomere maintenance; thus, dysregulating DDR pathways, such as ATM and ATR, can affect telomere hemostasis, therefore boosting their survival. Nano-based drug delivery systems represent immense potential for achieving different targeting strategies, and they are emerging as promising means for targeting the telomere/DDR axis. In this chapter, we discuss the orchestration between telomere biology, DDR pathways, and cancer progression. We also explore potential drug design sites and highlight cutting-edge nanomedicines that address these pathways in cancerous cells.