Extracorporeal shock wave therapy (ESWT) has been extensively studied for its multiple biological properties, and although it is widely applied in esthetical procedures, little is known about its effects on the epidermis and dermis. In this study, a histological and immunohistochemical study of the effects of ESWT was performed on rat skin. Forty-five female rats were treated with one or two sessions of ESWT and sacrificed on days 1, 7, 14, and 21 after treatment. The samples were histologically processed and then morphometric analyses were performed to assess the epidermis, dermis, and subcutaneous fat tissue thickness. Immunohistochemical reactions were also performed against the antibodies: basic fibroblastic growth factor (FGF2), its receptor (FGFR1), and α-smooth muscle actin. Slides were scanned and digitally assessed, to determine the microvessel density (MVD) and digital scoring of the immunohistochemical staining. The results showed that ESWT produced a significantly higher collagen content, MVD, and epidermis and dermis thickness than the control, non-treated group. Both in epidermis and dermis, FGF2 was overexpressed in the ESWT-treated groups, whereas FGFR1 was increased only in the group treated with two ESWT sessions at 21-days post-treatment. The ESWT-treated groups have also shown diminished thickness of subcutaneous fat tissue. In conclusion, ESWT induces neocollagenesis and neoangiogenesis, and upregulates the FGF2 expression, particularly in the groups treated with two sessions. Furthermore, it was demonstrated that overexpression of FGF2 on skins treated with ESWT seems to be a key role on its mechanism of action.