Documents from the 17th-18th centuries mention the location of the Church of Saints Cosmas and Damian as a suburb of Rostov. The church was situated on the main road to Yaroslavl. The lands by the lake were very fertile and over time became the property of wealthy merchants, such as the Pudovs and Timonins, as well as landowners and manufacturers like the Kekins and Shchotkins, and townspeople like the Makonins and Sveshnikovs. In the second half of the 18th century, the Holy Trinity Church, located in the area of the modern Tsikornaya sawmill, was closed. Its parish and utensils were transferred to the Church of Saints Cosmas and Damian. In the early 19th century, the road was moved, and the church was left off to the side. However, the church's territory expanded to the new road, where a chapel stood at the intersection of the alley and the street. With the blessing of Bishop Athanasius of Rostov and the efforts of the parishioners, the church was built of brick. Initially, in 1769, a chapel in honor of Saints Cosmas and Damian of Rome was consecrated in the warm part. Then the main altar of the summer church was consecrated in honor of the Most Holy Theotokos Odigitria. In 1775, under Priest Andrei, the construction of the church was completed, and on the day of the celebration of the icon of the Mother of God Odigitria, a chapel in the name of Tsar Constantine and Empress Helena was consecrated in the warm part. The construction and decoration of the church lasted six years. The records on the memorial crosses mention the participants in this endeavor, Priest Maxim Nikiforov and Deacon Athanasius.

Despite the consecration of the main altar in honor of the Most Holy Theotokos Odigitria, the church is more commonly referred to as the Cosmas-Damian Church. Historians note that the role of the Church of Saints Cosmas and Damian can be judged by the activities of the Yaroslavl Spiritual Consistory and the Rostov Spiritual Administration. The Cosmas-Damian Church is mentioned more frequently than other churches in Rostov. Its location ensured a large congregation and income opportunities. There was a cemetery for parishioners near the church.

According to data from 1908, the church owned 1812 square fathoms of land in Rostov and 8 desyatins 1875 square fathoms in the Rostov district. The church capital amounted to 2008 rubles 26 kopecks, and the parish capital was 8788 rubles 76 kopecks. The parish consisted of a priest and a psalmist. The congregation numbered 633 people from Rostov and the surrounding settlements. In the early 20th century, local historian A.A. Titov mentions the church, noting the icon of St. Prophet Elijah from 1664 and the miraculous icon of the Smolensk Mother of God from the 16th century. The iconostasis and icons date back to 1775.

For the first time in a printed publication, the icon of Odigitria is called miraculous, although there are no written testimonies of miracles. The icon of St. Prophet Elijah and the icon of Odigitria are part of the exhibition of ancient Russian art at the Rostov Kremlin Museum-Reserve. Also there is the icon of the Mother of God, the Burning Bush. A collection of ancient documents has been preserved in the State Archive of the Yaroslavl Region.

The wealth and significance of the church led to its closure in 1926, one of the first in the city. Parishioners delayed the closure for a year, using the right to file a cassation appeal. The city council decided to close the church in July 1925, but the final decision came a year later. The church was closed in July 1926, with part of the property transferred to a museum, part to the Abraham Religious Society, and part destroyed.

Old-timers remember not so much the closure of the church and the repressions, but the ringing of the bells. With the bell, the church's life and services ceased. The church building became a pioneer club, during the war, a barracks, and later, housing. In recent decades, the church was known as a collection point for glass containers.

The revival of the church began in 1995. The restoration was undertaken by the Patriarchal Representation of Rostov. Currently, the warm refectory part of the church is used for services. The holy altar is dedicated to Saints Cosmas and Damian of Asia Minor and was consecrated on October 13, 2002, by Archpriest Vyacheslav Savinykh. In January 2004, the parish of the Church of Saints Cosmas and Damian of the Yaroslavl Diocese of the Russian Orthodox Church was established.