Abstract Background A growing link between prenatal exposure to misoprostol (PEM) and Moebius syndrome (MS) or sequence has been reported. Our objectives were to describe the craniofacial clinical manifestations associated with MS and to determine the frequency of PEM, comparing cases of exposure and nonexposure. Methods A descriptive, cross‐sectional study of 140 patients with MS. Clinical evaluations, as well as 140 interviews with mothers residing in 39 cities or districts of Colombia, were carried out between April 2008 and May 2018. Additionally, previous clinical history of each case was reviewed. Results The average age of the patients with MS was 8.4 years (29 days to 48 years). All of them presented facial nerve involvement and abducens, 112 (80.8%) with bilateral facial paralysis. 98.5% presented craniofacial disorders, and there were no significant differences between those exposed and not exposed to misoprostol. Forty‐seven percentage of patients (64 cases) presented PEM, in 98.4% of which abortion had been intended. Conclusion PEM could have an influence in the appearance of new cases of MS by increasing the frequency of bleeding during gestation, without increasing the number of associated craniofacial malformations. We present the biggest series on MS and craniofacial findings in the literature, along with a meaningful reference for its understanding. Level of Evidence 3b.