Üsküdar holds more than 180 mosques — a density that reflects its role as one of the most religiously significant districts in Ottoman Istanbul. The imperial family poured patronage into this shore. The Mihrimah Sultan Mosque, sometimes called the İskele (Dock) Mosque because it stands at the ferry landing, was built for a daughter of Suleiman the Magnificent; the Şemsi Pasha Mosque beside it was built for one of Suleiman's viziers. Both were designed by Mimar Sinan, the great architect of the Ottoman classical period. Uphill, the Atik Valide Mosque — also Sinan's work — was commissioned by the mother of Sultan Murat III.

Women of the imperial harem were particularly significant as patrons of Üsküdar's religious buildings. The Yeni Valide Mosque, opposite the ferry terminal, was commissioned by the mother of Sultan Ahmet III. The Çinili (Tiled) Mosque further uphill and the newer Çamlıca Mosque on the hill above the district continue a tradition of sacred construction that spans five centuries.

Alongside its mosques, Üsküdar has long been a center of Sufi spiritual life. Aziz Mahmud Hudayi (1541–1628), founder of the Jelveti Sufi order, is buried in the neighborhood that bears his name; his lodge was one of the most important spiritual centers of Ottoman Istanbul. The Nasuhi Efendi lodge at Doğancılar served the Nasuhiyye Khalwati order — and its founder, Nasuhi Efendi, happened to be the grandfather of Ahmet Ertegun, the Turkish-American businessman who co-founded Atlantic Records in New York and signed artists including Ray Charles, Led Zeppelin, and the Rolling Stones. The Ertegun family is buried at the Özbekler Tekkesi in Sultantepe.

The Üsküdar Mevlevi dergah — the second such lodge in Istanbul after the one in Galata — was built in 1790 by Sheikh Numan Dede. It now functions as the Classic Turkish Arts Foundation. These institutions were not simply places of worship; they were social networks, schools, and cultural anchors for the communities around them.

During the Crimean War of the 1850s, the Selimiye Barracks in Üsküdar became a British military hospital, and it was here that Florence Nightingale arrived in November 1854 with a team of nurses to address catastrophic mortality rates among British soldiers. She found a facility without basic sanitation, clean water, or adequate supplies. Working against institutional resistance, she implemented systematic reforms in hygiene and nutrition, and the mortality rate dropped dramatically.

Nightingale's work at Scutari — as the British called Üsküdar — became the foundational act of modern professional nursing. The Florence Nightingale Museum inside the Selimiye Barracks preserves items associated with her time there. Beylerbeyi Palace, a short distance along the Bosphorus shore, tells a different story of the nineteenth century: built for Sultan Abdulaziz in the 1860s, it became the final place of confinement for Sultan Abdul Hamid II, held under house arrest there until his death in 1918.

Üsküdar's religious landscape extends beyond its mosques. Greek Orthodox, Armenian, and Jewish communities have all maintained places of worship here for centuries. The Kuzguncuk neighborhood on the Bosphorus shore holds two synagogues — Bet Nissim (built in the 1840s) and Bet Yaakov (built in 1878) — and Armenian and Greek Orthodox churches, an unusual concentration of minority religious life in a single district.

The notable residents list for Üsküdar reads like a cross-section of Istanbul's cosmopolitan history: Maximus the Confessor, the seventh-century Byzantine theologian who entered a monastery at Chrysopolis; Calouste Gulbenkian, the Armenian oil magnate once described as the richest man in the world; Mehmet Akif Ersoy, who wrote the Turkish national anthem; Halide Edib Adıvar, the novelist and nationalist feminist; and Bülent Ersoy, the celebrated transgender singer of Ottoman classical music. What connects them is this shore — the Asian side, the older bank, the place the ferry delivers you to every time you cross.