The detrimental implications of tobacco smoke on systemic health have been widely established during the past few decades. Nonetheless, increasing evidence has begun to shed more light on the serious impact that smoke exposure could also have on mammal reproductive health in terms of overall ovarian dysfunction and gestation. A variety of these complications seem to be causally related to specific chemical substances contained in cigarette smoke and their possible effects on ovarian tissues and cells, such as granulosa cells. Granulosa cells represent the functional unit of the ovary and are able to establish a bidirectional cross-talk relationship with the oocyte during folliculogenesis, which makes them vital for its correct growth and development. Based on these premises, the current review focuses on the presence of related smoke-induced damages in granulosa cells. Data have been grouped according to the studied tobacco constituents and the molecular pathways involved, in order to synthesize their impact on granulosa cells and fertility. Attention is further brought to the correlation between electronic cigarettes and female reproduction, although there have been no investigations so far regarding e-cigarette-related granulosa cell exposure. We summarize how tobacco constituents are able to cause alterations in the “life” of granulosa cells, ranging from luteal steroidogenesis and follicular loss to granulosa cell apoptosis and activation of the autophagic machinery. Further studies have been conducted to elucidate the relationship between lifestyle and fertility as to reduce the morbidity connected with infertility.