To date, there is no consensus on the surgery strategies of cranioplasty (CP) and ventriculoperitoneal shunt (VPS) placement. This meta-analysis aimed to investigate the safety of staged and simultaneous operation in patients with comorbid cranial defects with hydrocephalus to inform future surgery protocols. A meta-analysis of PubMed, Ovid, Web of Science, and Cochrane Library databases from the inception dates to February 8, 2023 adherent to PRISMA guidelines was conducted. The pooled analyses were conducted using RevMan 5.3 software. The outcomes included postoperative infection, reoperation, shunt obstruction, hematoma, and subdural effusion. Of the 956 studies initially retrieved, 10 articles encompassing 515 patients were included. Among the total patients, 193 (37.48%) and 322 (62.52%), respectively, underwent simultaneous and staged surgeries. The finding of pooled analysis indicated that staged surgery was associated with lower rate of subdural effusion (14% in the simultaneous groups vs. 5.4% in the staged groups; OR = 2.39, 95% CI: 1.04-5.49, p = 0.04). However, there were no significant differences in overall infection (OR = 1.92, 95% CI: 0.74-4.97, p = 0.18), central nervous system infection (OR = 1.50, 95% CI: 0.68-3.31, p = 0.31), cranioplasty infection (OR = 1.58, 95% CI: 0.50-5.00, p = 0.44), shunt infection (OR = 1.30, 95% CI: 0.38-4.52, p = 0.67), reoperation (OR = 1.51, 95% CI: 0.38-6.00, p = 0.55), shunt obstruction (OR = 0.73, 95% CI: 0.25-2.16, p = 0.57), epidural hematoma (OR = 2.20, 95% CI: 0.62-7.86, p = 0.22), subdural hematoma (OR = 1.20, 95% CI: 0.10-14.19, p = 0.88), and intracranial hematoma (OR = 1.31, 95% CI: 0.42-4.07, p = 0.64). Moreover, subgroup analysis failed to yield new insights. Staged surgery is associated with a lower rate of postoperative subdural effusion. However, from the evidence of sensitivity analysis, this result is not stable. Therefore, our conclusion should be viewed with caution, and neurosurgeons in practice should make individualized decisions based on each patient's condition and cerebrospinal fluid tap test.