Background: Surgical site infections (SSIs) remain a conundrum for neurosurgeons. This study examines the efficacy and outcome of vacuum sealing drainage (VSD) in the treatment of pyogenic SSIs following intracranial neurosurgery. Methods: Twenty patients with SSIs, who received surgical intervention, were treated retrospectively with VSD during the past five years. Primary surgical procedure types, SSI types, VSD replacements, pathogenic germs, antibiotic therapy, and infection control were reviewed and discussed. Results: Of the 20 infections, 13 (65%) were extradural and 7 (35%) were extradural SSIs combined with intracranial infections (including 5 meningitis, 1 subdural abscess, and 1 brain abscess). All the patients consented to medical device implantation (including 5 titanium webs, 6 bone flap fixation devices, and 12 duraplasties), most of which were removed during debridement. The median duration from primary surgical procedure to an SSI diagnosis was 19 days (range: 7 to 365 d). All the patients also agreed to debridement and VSD treatment; VSD was replaced 0 to 5 times (median, one time) every 4 to 7 days and kept for 4 to 35 days (median, 14 d). Seven (35%) patients had defined bacterial infections, with Staphylococcus aureus being the dominant infection. The deployed standard VSD and antibiotic treatment ensured full recovery from SSIs, including from intracranial infections: 14 (70%) patients had recovered fully by follow-up, and no infection-associated death was registered; 6 (30%) patients died of severe primary affections. Conclusion: VSD-assisted therapy is safe and effective against SSIs after intracranial neurosurgery.