The Golden Horn is the estuary of two modest streams — the Alibey and the Kağıthane Creeks — but its significance has always been disproportionate to its source. Recent excavations during construction of the Yenikapı subway station and the Marmaray tunnel project uncovered ancient ports, storage facilities, and trade ships buried beneath Istanbul, placing significant human settlement here as far back as 6700 BC. A more urbanized presence appears in the archaeological record by at least the 7th century BC. Emperor Constantine I recognized the harbor's value when he established his new capital, Nova Roma — later Constantinople — on the existing city of Byzantium in the 4th century AD. The deep, sheltered waters that had drawn settlers for millennia would now serve an empire. The Eastern Roman Empire based its naval headquarters here and built walls along the shoreline to protect the city from seaborne attack. Whoever controlled this inlet controlled the city.

To guard the entrance to the Horn, the Byzantines stretched a massive iron chain across the water from Constantinople to the Tower of Galata on the northern shore. Three times in history, forces found ways around it. In the 10th century, the Kievan Rus' dragged their longships overland, out of the Bosphorus, around Galata, and relaunched them inside the Horn — only to be destroyed by Greek fire, the Byzantine naval weapon whose exact composition remains disputed today. In 1204, Venetian ships in the Fourth Crusade rammed the chain with enough force to break it. In 1453, the Ottoman Sultan Mehmed II — unable to break through by brute force — chose the same overland strategy as the Rus': he had his ships dragged across Galata on greased logs and lowered into the estuary. Constantinople fell days later. The chain, in the end, bought time but not salvation.

Following the Ottoman conquest, Mehmed II reshuffled the Horn's communities. Ethnic Greeks were resettled in the Phanar neighborhood — today's Fener — along the western shore. The Jewish community of Balat, established in Byzantine times, largely remained, though some chose to leave after the conquest. A generation later, the balance shifted again: when Sultan Bayezid II invited the Jews expelled from Spain under the Alhambra Decree to resettle in the Ottoman Empire, Balat was repopulated. The Horn's shores became a mosaic of faith and ethnicity that would characterize Istanbul for centuries. In 1502, Leonardo da Vinci drew up plans for a single-span bridge of 240 meters across the Golden Horn for Bayezid II. The bridge was never built — the design was considered too ambitious for the engineering of the day — but Leonardo's drawings survive in Milan. In 2001, a smaller footbridge based on his design was built near Ås, Norway, by artist Vebjørn Sand.

For much of the 20th century, the Golden Horn paid a heavy environmental price for Istanbul's industrialization. Factories, warehouses, and shipyards lined its shores, and by the time serious attention turned to the problem in the 1980s, the water was heavily polluted and the shoreline degraded. Cleanup efforts came in two main phases: under Mayor Bedrettin Dalan in the 1980s and under Mayor Recep Tayyip Erdoğan in the 1990s. Fish and wildlife largely returned. The Haliç Shipyard — the oldest shipyard in the Horn, founded by Mehmed II in 1455, and sometimes described as one of the oldest in the world — fell into disrepair after the 1960s but has since become the site of Tersane Istanbul, a major redevelopment project announced in 2019 and partially opened in October 2021, bringing arts venues and hospitality to a formerly industrial stretch of waterfront.

Today the Golden Horn is crossed by four bridges. Moving from upstream to downstream: the Haliç Bridge (completed 1974), the Atatürk Bridge (also called the Unkapanı Bridge, completed 1940), the Golden Horn Metro Bridge (a pedestrianized railway crossing completed 2014), and the Galata Bridge in its fifth incarnation (completed 1994), where anglers line the railings and the lower level holds fish restaurants. An hourly ferry service connects Üsküdar and Karaköy with suburbs along the estuary. The western shore now runs alongside parks. The painter Ivan Aivazovsky captured the Horn's golden evening light in multiple works; G.K. Chesterton's poem 'Lepanto' placed a lord laughing on the Golden Horn in the sun. The estuary that has turned back armies and buried ancient ships now draws visitors who come simply to watch the light change on the water.