The architectural ensemble of the Makaryev-Zheltovodsky Monastery was mainly formed between 1661 and 1677. Art historians note that this contributed to the unique integrity of the monastery's buildings. In the early 1620s, a wooden church dedicated to the Holy Trinity stood on the site of the current Trinity Cathedral. However, it did not correspond to the status of the monastery on the Volga, and soon the church authorities decided to build a larger temple. The new cathedral, consecrated in honor of the Holy Trinity, became the central architectural and meaningful dominant of the monastery. Its construction took place from 1651 to 1658 and is associated with the name of Patriarch Nikon. Although it is not precisely known what role he played in the construction of the stone temples of the monastery, his personal connection to the monastery was significant, as he lived here as a novice in his youth.

The architectural solution of the Trinity Cathedral reflects the concept of temple architecture promoted by Nikon, which involved a rejection of tent-like finishes and an orientation towards the Assumption Cathedral of the Moscow Kremlin. The builders of the Trinity Cathedral of the Zheltovodsky Monastery followed this model. It is believed that the construction of the stone temples was overseen by Maxim Apsin, a master from Moscow. The cathedral was an ambitious project for its time, although it did not surpass the Assumption Cathedral in size, it was larger than the Transfiguration Cathedral of the Novgorod Kremlin.

From 1977 to 1983, restoration work was carried out in the cathedral. The metal crosses were cleaned and painted, the domes were repaired, the roof was covered and painted, the brickwork was restored, the windows were glazed, and the rafter structures were replaced. Ground reinforcement under the cathedral was also completed. In the 1980s, the cathedral nearly ended up underwater due to the construction of the Cheboksary Hydroelectric Power Station. Currently, the Holy Trinity Cathedral is under state protection and is the only one in the Nizhny Novgorod region where 17th-century frescoes have been preserved. In the 2000s, the restoration of icons was carried out by Nizhny Novgorod icon painter Alexey Antsiferov. On August 7, 2007, the head of the venerable Makary was transferred to the monastery, and on the same day, Archbishop Georgy consecrated the Holy Trinity Cathedral.