One of the historical periods of Iran that can be studied for contagious diseases and how they spread, is the late Qajar period. The city of Mashhad, after Tehran and Tabriz, had a special place among Russian and English governments in the Qajar period as one of the significant religious, political and economic centers in Iran due to Imam Reza’s holy shrine, a large population and great geographical scale. The central governments’ incompetence in preventing the outbreak of contagious diseases and lack of essential amenities, caused many lives to be lost all over Iran and especially Mashhad during the Qajar period. Hence, the neighbor governments such as Russia, ordered for quarantines to be set up at the borders and dispatched doctors to stop diseases’ from reaching Russian lands. However, these attempts did not prevent the deaths of people in the border areas, especially in Mashhad, from diseases such as cholera, plague, smallpox, typhus, flu and other diseases. In this study, we investigate and explain the subjects: disease outbreaks, the problem of commerce, quarantine and its outcomes at the end of Qajar period, between the years 1892 and 1921 AD in Mashhad, with the help of historical and documentary sources using an analytical and medical historiography method.