[7] Galena typically is found in hydrothermal veins in association with sphalerite, marcasite, chalcopyrite, cerussite, anglesite, dolomite, calcite, quartz, barite, and fluorite.

In the United States, it occurs most notably as lead-zinc ore in the Mississippi Valley type deposits of the Lead Belt in southeastern Missouri, which is the largest known deposit,[2] and in the Driftless Area of Illinois, Iowa and Wisconsin, providing the origin of the name of Galena, Illinois, a historical settlement known for the material.

Galena also was a major mineral of the zinc-lead mines of the tri-state district around Joplin in southwestern Missouri and the adjoining areas of Kansas and Oklahoma.

[2] Galena is also an important ore mineral in the silver mining regions of Colorado, Idaho, Utah and Montana.

Zinc, cadmium, iron, copper, antimony, arsenic, bismuth and selenium also occur in variable amounts in galena.

[8] Galena exposed to acid mine drainage can be oxidized to anglesite by naturally occurring bacteria and archaea, in a process similar to bioleaching.

[22] One of the oldest uses of galena was to produce kohl, an eye cosmetic now regarded as toxic due to the risk of lead poisoning.

[23] In Ancient Egypt, this was applied around the eyes to reduce the glare of the desert sun and to repel flies, which were a potential source of disease.

[24] In pre-Columbian North America, galena was used by indigenous peoples as an ingredient in decorative paints and cosmetics, and widely traded throughout the eastern United States.