A 51-year-old woman with end-stage renal disease undergoing hemodialysis three times per week reported the onset of a severe, pulsatile headache occurring 2–3 hours into dialysis and lasting up to 8 hours post-session. The pain, predominantly frontal and unilateral, significantly impaired her quality of life and was only partially relieved with medication. Her neurological examination and electrolyte levels were normal, and no significant blood pressure fluctuations were observed. This case exemplifies dialysis headache, a prevalent but often overlooked complication of hemodialysis. Dialysis headache affects 6.6% to 70% of patients and is characterized by a headache that arises during or after hemodialysis and resolves within 72 hours. The underlying mechanisms are multifactorial, involving endothelial dysfunction, electrolyte disturbances, blood pressure variability, and the release of vasoactive substances such as nitric oxide and calcitonin gene-related peptide (CGRP). While dialysis headache may resemble primary headache disorders, its strong temporal association with dialysis distinguishes it as a separate clinical entity. Diagnosis relies on the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria, with differential diagnoses including hypertensive crisis, caffeine withdrawal, and dialysis disequilibrium syndrome. Current treatment options remain limited, primarily focusing on optimizing dialysis parameters and managing symptoms with common analgesics. Emerging research suggests that CGRP-targeted therapies may offer new therapeutic possibilities. Despite advancements in dialysis technology, dialysis headache continues to be a major concern, underscoring the need for further research into effective preventive and treatment strategies. Increased awareness and targeted interventions could improve the quality of life for patients undergoing long-term hemodialysis.