Lumbar puncture is a frequent procedure performed by physicians from several disciplines to help establish a diagnosis and treatment for several diseases. Post-lumbar puncture headache (PLPH) is a frequent complication that typically lasts for a couple of days and can be severe enough to immobilize the patient and to require therapy. There are several risk factors identified, pain characteristics, and characteristic findings on spinal and head magnetic resonance imaging. There are several procedural factors that have been identified to be of consequence in attenuating the PLPH incidence, specifically the needle type and size used for this procedure. Once PLPH occurs, the clinician should treat it conservatively with bed rest, analgesics and increased fluids intake, especially caffeine-containing beverages, as it can dramatically affect the patient’s wellness. If the pain is severe and disabling and does not respond to conservative treatment, a blood patch should be considered at least 24–48 h following the LP. Epidural blood patch is a safe and rapidly effective treatment in experienced hands. Furthermore, patients who developed PLPH should be advised to contact the medical staff in case of changes in the characteristics of headaches. When a patient who was diagnosed with PLPH has a change in the pain character, or additional neurological manifestations appear, an urgent brain CT/head MRI should be performed to exclude rarer life-threatening intracranial complications.