Tobacco smoking is still a widespread habit in pregnant and breastfeeding women. While the role of these risk factors on neonatal outcomes has been deeply studied, their effect on human milk composition is still not completely clear. This study aimed to report the most up to date evidence about the alteration of breast milk composition of smoking breastfeeding mothers compared to non-smoking ones. We performed a systematic review by searching PubMed, Embase, and Cochrane Library databases. Evaluated data were extracted and critically analyzed by two independent authors. PRISMA guidelines were applied, and the risk of bias was assessed (ROBINS), as was the methodological quality of the included studies (GRADE). After applying the inclusion criteria, we included 20 studies assessed as medium or high quality. In all the studies, we analyzed data regarding 1769 mothers (398 smokers and 971 nonsmokers). Smoking was associated with a lower content of lipids, calories, and proteins. Moreover, it was characterized by decreased antioxidant properties and an altered immune status. Smoking during pregnancy and breastfeeding is significantly associated with an alteration of milk metabolic properties. Further studies are needed to investigate how these changes can alter newborns' development and outcomes and which molecular patterns are involved.