The colony was initially managed by the Deutsche Neuguinea-Kompagnie or German New Guinea Company, a commercial enterprise that christened the territory Kaiser-Wilhelmsland.

Along its course it receives numerous tributaries from the Bewani and Torricelli Mountains to the north and the Central Range to the south, including the Yuat River formed by the Lai and the Jimmi.

Unlike many other large rivers, the Sepik has no delta whatsoever, but flows straight into the sea, about 100 km (62 mi) east of the town of Wewak.

[9][14] The Sepik basin is largely an undisturbed environment, with no major urban settlements, or mining and forestry activities, in the river catchment.

[27] European contact with the river started in 1885, shortly after Germany established colonial control over German New Guinea or Kaiser Wilhelmsland.

[28] For the most part, German interest in the river was mainly to explore its economic potential, to collect artifacts, and to recruit native laborers to work on coastal and island copra plantations.

[28] In 1887, the Samoa returned with another scientific expedition as well as a dozen Malays, eight men from the island of New Britain, and, two members of the Rhenish Missionary Society.

[28] After the first World War the Australian government took trusteeship of the German colony, creating the Territory of New Guinea, and the Sepik region came under their jurisdiction.

[28] In 1923 journalist Beatrice Grimshaw attached herself to an expedition, and claimed to be the first white woman to ascent the Sepik, commenting on the widespread use of "pidgen-English" as a lingua franca.

[34] In 1935 Sir Walter McNicoll, the new administrator of the Territory of New Guinea, travelled up length of the Sepik to "have a look at the river people and the kind of country along the banks".

[35] Despite the thorough exploration of the Sepik and the river basin by Europeans starting with the 1880s, and the extraordinarily keen knowledge of the region by local people and communities, many travelers today still see their tourism in the area as heroic efforts.

Part of this fantasy is that the river tribes are often said to have "little contact with the modern world," as the Los Angeles Times put it as late as 2017.

After nearly drowning in a section of rapids near Telefomin, they decided to walk through the jungle, following the river until it was calm enough to take a dugout canoe the remaining 900 kilometres to the Bismarck Sea.

"[38] Also in 2010, the painter Ingo Kühl, accompanied by the local artist Tomulopa Deko, traveled from Goroka via Madang, Wewak and Maprik to Pagwi and from there on the Sepik upriver to Ambunti and to the villages of Maliwai, Yambon and Yessan.

By the end of the war though, the Japanese had been completely surrounded after Hollandia and Aitape in Netherlands New Guinea were captured by Allied forces in April 1944 during Operations Reckless and Persecution.

[40][41] The Aitape-Wewak campaign, the battle to defeat the remaining forces by the Australian Army, was hard-fought and drawn out due to the terrain lasting until the end of the war in August 1945.

The numerous different tribes living along the river produce magnificent wood carvings, clay pottery and other art and craft.