Background: Autoimmunity is believed to play an important causative role in the pathogenesis of epilepsy. There are evidences for the presence of autoantibodies in patients with epilepsy. To date, many studies have assessed the presence of antiphospholipid antibodies (aPLs) in epilepsy patients, though the relationship has been inconclusive. Aims: The aim of this systematic review and meta-analysis was to evaluate the presence of aPLs in epileptic patients as compared to healthy controls. Methods: Five electronic databases (PubMed, Web of Science, Embase, Scopus and Google Scholar) were searched systematically. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects model. Quality assessment was carried out by using the modified 9-star Newcastle-Ottawa Scale (NOS). L'Abbé plots were generated to visually inspect heterogeneity while publication bias was evaluated via visualization of contour- enhanced funnel plots, and Begg's and Egger's tests. Results: Based on the inclusion criteria, 14 studies were selected involving 1248 epilepsy patients and 800 healthy controls. The majority of epilepsy was categorised as generalised or partial and none had comorbidity with autoimmune diseases. Significant presence of both anticardiolipin (aCL) antibodies (OR: 5.16, 95% CI: 3.21–8.28, p < 0.00001) and anti-β2- glycoprotein I (anti-β2-GPI) antibodies (OR: 2.95, 95% CI: 1.07–8.11, p = 0.04) exhibited comorbid association with epilepsy patients as compared to healthy controls. Subgroup analyses revealed that presence of aCL antibodies was more specifically observed in paediatrics (OR: 4.57, 95% CI: 2.57–8.15, p < 0.00001) than adults (OR: 4.24, 95% CI: 1.80–10.01, p = 0.001). The odds of aCL antibody presence was higher in partial epilepsy patients (OR: 7.88, 95% CI: 3.23–19.24, p < 0.00001) than that of generalised (OR: 3.76, 95% CI: 2.15–6.59, p < 0.00001) and in Asian epileptic patients (OR: 9.56, 95% CI: 2.69–33.95, p = 0.0005) than Europeans (OR: 4.35, 95% CI: 2.74–6.92, p < 0.00001). The presence of anti-β2-GPI antibodies was significant in paediatric (OR: 6.44, 95% CI: 1.39–29.89, p = 0.02) and African population with epilepsies (OR: 10.59, 95% CI: 1.22–92.25, p = 0.03). NOS of the majority of the studies (11/14) indicated a high methodological quality. No substantial heterogeneity was observed either from the quantitative analysis or from the L'Abbé plots while no significant publication bias was detected from funnel plots; Begg's and Egger's tests. Conclusion: Since none of the epilepsy subjects exhibited any comorbid autoimmune disorders, significant presence of aCL and anti-β2-GPI antibodies indicate towards their contribution in immune-mediated general pathogenesis of epilepsy.