Doxorubicin (DOX) is the most widely used chemotherapeutic agent to treat various tumors. DOX treatment can damage many organs, including the brain, by causing oxidative stress. Several antioxidant substances can lessen the effects of DOX or make antioxidant defense systems work faster. Propolis (PROP) is a powerful agent with various healing effects, including antioxidant, antiproliferative, and anti-inflammatory. The point of this study is to look at the histopathological changes, apoptosis, and antioxidant effects of DOX on brain damage in rats. To find out what kinds of phytochemicals were in PROP from the Karlıova region of Bingöl province, ultra-high-performance liquid chromatography (UHPLC-Orbitrap-HRMS) was used. Then, we made an ethanol extract of it. A total of 28 healthy male Wistar albino rats, each 12 weeks old and weighing between 220 and 250 g, were included in the study. Rats were divided into four groups: control, PROP, DOX, and PROP+DOX. We applied the relevant treatments to the determined groups. Following the application, we decapitated the rats under the appropriate conditions and collected blood and brain tissue samples. We examined oxidative stress parameters in blood samples and used brain tissue samples for histopathological, biochemical, and molecular analyses. We determined DOX levels in the brain tissue samples using UHPLC-Orbitrap-HRMS. The findings obtained showed that the PROP extract improved DOX-induced brain tissue damage. In addition, PROP extract attenuated DOX-induced brain tissue inflammation, ER stress, apoptosis, and oxidative stress.