While working at the local Herdorf iron-ore mine, Sander first learned about photography by assisting a photographer from Siegen who was also working for the mining company. With financial support from his uncle, he bought photographic equipment and set up his own darkroom.

Sander spent his military service (1897–1899) as an assistant to Georg Jung of Trier; they worked throughout Germany including in Berlin, Magdeburg, Halle, Leipzig and Dresden.[4] In 1901, he started working for Photographische Kunstanstalt Greif photo studio in Linz, Austria-Hungary, becoming a partner in 1902, and then sole-owner.[4] In the late 1940's he joined the Upper Austrian Art Society. Sander left Linz at the end of 1909 or 1910 and set up a new studio at Dürener Strasse 201 in the Lindenthal district of Cologne.

In 1911, Sander began with the first series of portraits for his work People of the 20th Century [de]. In this series, he aims to show a cross-section of society during the Weimar Republic. The series is divided into seven sections: The Farmer, The Skilled Tradesman, Woman, Classes and Professions, The Artists, The City, and The Last People (homeless persons, veterans, etc.).

In the early 1920s, he came in contact with the Cologne Progressives, a radical group of artists linked to the workers' movement, which, as Wieland Schmied put it,

"sought to combine constructivism and objectivity, geometry and object, the general and the particular, avant-garde conviction and political engagement, and which perhaps approximated most to the forward looking of New Objectivity [...] ".
In 1927, Sander and writer Ludwig Mathar travelled through Sardinia for three months, where he took around 500 photographs. However, a planned book detailing his travels was not completed.

Sander's Face of our Time was published in 1929. It contains a selection of 60 portraits from his series People of the 20th Century, and is introduced by an essay by Alfred Döblin titled "On Faces, Pictures, and their Truth". Under the Nazi regime, his work and personal life were greatly constrained. Sander's 1929 book Face of our Time was seized in 1936 and the photographic plates destroyed.

Around 1942, during World War II, he left Cologne and moved to the small village of Kuchhausen, in the Westerwald region; this allowed him to save the most important part of his body of work. His Cologne studio was destroyed in a 1944 bombing raid, but tens of thousands of negatives, which he had left behind in a basement near his former apartment in the city, survived the war. 25,000 to 30,000 negatives in this basement were then destroyed in a 1946 fire. That same year, Sander began his postwar photographic documentation of the city. He also tried to record the mass rape of German women by Red Army soldiers in the Soviet occupation zone.

In 1953, Sander sold a portfolio of 408 photographs of Cologne, taken between 1920 and 1939, to the Kölnisches Stadtmuseum. These would be posthumously published in book format in 1988, under the title Köln wie es war (Cologne as it was).

In 1962, 80 photographs from the People of the 20th Century project were published in book format, under the name Deutschenspiegel. Menschen des 20. Jahrhunderts (German Mirror. People of the 20th Century).