Multiple sclerosis (MS) is a common, severe neurological disease that affects millions of people worldwide. Nevertheless, the actual cause of MS remains unknown. Smoking has been studied with respect to MS development and progression. The objectives of this review were to examine the relationship between smoking and MS and to understand the possible molecular mechanisms underlying the association. PubMed was searched for articles related to the study topic published between 2012 and 2020 using the search terms “multiple sclerosis,” “smoking,” “risk factors,” “cigarettes,” and “molecular mechanisms.” Studies show a significant relationship between smoking and the risk of MS. Furthermore, smoking has been linked to the progression of MS at the patient and population levels. However, the underlying mechanism remains to be explored in further studies; researchers still disagree on how the relationship between smoking and MS arises in different populations. Evidence from randomized controlled trials, systematic reviews, and epidemiological studies shows that smokers have a higher risk of developing MS and experiencing related adverse symptoms and complications.