Once, this temple, one of the oldest in Moscow, was the center of the district and looked significantly larger than it does now.

In the 14th century, there was a palace village of Naprudnoye at this site, surrounded by ponds and a river that was a tributary of the Neglinnaya. The Tsar's Woloviy court appeared here, and the surroundings of Naprudnoye became popular for falconry. The legend of the creation of the Church of Saint Tryphon is connected with this. According to tradition, Prince Patrikeev lost his falcon during a hunt and, fearing the wrath of the monarch (according to some sources Ivan III, according to others, Ivan IV the Terrible), prayed to Saint Tryphon. The falcon was found thanks to the saint, and in gratitude, Prince Patrikeev built the Tryphon Church. In the late 16th and early 17th centuries, a fresco depicting Saint Tryphon on horseback with a falcon on his hand appeared in the interior of the temple.

The Tryphon Church is a single-domed, pillarless temple with a cross vault. The dating of the stone church is disputed among researchers. Some attribute it to the late 15th century, based on an epitaph and the use of white stone. The year 1492 is even mentioned. Others believe that the temple was built in the mid or second half of the 16th century. S.V. Zagraevsky suggested that the church was erected in the mid-1470s or 1480s.

In the 18th century, a refectory with an altar dedicated to Saint Nicholas the Wonderworker and a bell tower were added to the church. In the 19th century, the Metropolitan of Montenegro gifted the church a relic of Saint Tryphon, embedded in an icon. In 1861, a second altar in honor of Philaret the Merciful, the patron of the Metropolitan of Moscow Philaret, appeared in the refectory.

At the turn of the 19th and 20th centuries, the church underwent significant changes and expansions. In 1889 and 1892, a second bell tower in the pseudo-Russian style was built according to the design of architect P.P. Zykov, and in 1894 and 1898, a new refectory was constructed. In 1911, a new marble iconostasis with Royal Gates, created by architect F.O. Shekhtel, was installed. However, after the church was closed in 1932, the interiors were lost.

The icon of Saint Tryphon with a relic has survived, as it was transferred to the Church of the Sign in the Pereyaslavskaya Sloboda, which remained open in the 20th century. After the closure of the Tryphon Church, it lost all the additions from the 18th and 20th centuries and returned to its original size. Thanks to restorers, the ancient part of the building was preserved. The fresco depicting Saint Tryphon was transferred to the Tretyakov Gallery. In 1947 and 1948, during restoration organized by L.A. David, the historical shape of the dome was restored, and a small bell tower was created. Hospital buildings grew around the church, and the site of the lost altars is marked by wooden crosses.