Surgical site infection (SSI) after pilonidal disease surgery can lead to serious complications. We systematically searched the PubMed, Scopus, and ClinicalTrials.gov databases for studies evaluating the use of antimicrobials as an adjunct to pilonidal disease surgery. We identified 12 eligible studies [nine randomized controlled trials (RCTs), three retrospective cohort studies], enrolling a total of 1,172 patients. No difference was observed when single-dose prophylaxis was compared to no prophylaxis or to a long course of antibiotics (seven studies, 690 patients). Similarly, gentamicin collagen sponges (GCS) did not appear to be beneficial when compared with no GCS (with primary or secondary closure; four studies, 402 patients). One study (80 patients) reported faster healing and lower SSI and recurrence rates with GCS than a 7-day course of antibiotics. The clinical heterogeneity precluded a formal meta-analysis. Although the generalization of our findings may be limited by the relative paucity and clinical heterogeneity of the existing studies, prophylactic antibiotics or GCS did not appear to be beneficial in promoting healing or reducing SSI or recurrence rates. Large, double-blind, placebo-controlled RCTs are warranted in order to further elucidate this issue.