Objectives Post dural puncture headache (PDPH), since it is first described by August Bier in 1898, remains a common complication in spinal anesthesia (SA). Many pharmacological agents are suggested for PDPH management as acetaminophen, caffeine, non-steroidal antiinflammatory drugs, corticosteroids, and sumatriptan. Aim The aim of this study is to compare between the prophylactic effect of each of; aminophylline, gabapentin, and neostigmine added to atropine on the occurrence of PDPH after caesarean section (CS) under SA. Subjects and Methods This prospective randomized controlled clinical study was carried out 75 pregnant female patients 20-40 y, 60-100 kg. ASA physical status II undergoing elective CS. Patients were randomly divided into 3 groups (25 patients in each); group A: received 250 mg aminophylline IV immediately after delivery of the infant, group B: received IV neostigmine 20 µg/kg added to atropine 10 µg/kg immediately after delivery of the infant and group C: received 3 capsules gabapentin 300 mg; the 1st before SA by 2 h with sip of water, the 2nd after CS by 6 h and the 3rd after 14 h from CS. Results The incidence of PDPH was lower in group A (8% vs 40% in group B and 24% in group C. The onset of PDPH was significantly delayed in group C than group A and in group C than B, but insignificant between group A and B. The duration of PDPH and total dose of analgesic requirement was significantly lower in group A than group B and C and in group B than C. Heart rate (HR) showed significant increase in group A (post aminophylline than pre) only. HR in the other groups and mean arterial blood pressure showed insignificant difference among the three groups (between pre and post administration of drugs). As regards VAS, there was no significant difference in the three groups at 3 h. There was significant difference among the three groups at 6, 12, 24, 36, 48 and 72 h. (between group A & B from 24h up to 72h, between group A & C from 6 up to 72h and between group B & C at 6 h only (delayed onset with neostigmine)). Side effects were minimal and tolerable. Conclusion Aminophylline reduced the incidence and duration of PDPH after CS under SA more than gabapentin and neostigmine with less analgesic requirement and minimal side effects. Also, neostigmine was superior than gabapentin in delaying the onset and decreasing the duration of PDPH.