Mother Hildegard Dubnick, who comes from the USA, will step down after five years in office on Palm Sunday, 24 March.
This was announced by the abbey and the diocese of Eichstätt on Thursday evening.
Prioress Fides Nossek will assume interim leadership until a new head is elected.
The reason for Dubnick's departure is cultural differences.
Dubnick explained: "During the last five years, I realised that my idea of Benedictine life - as I know it, value it and want to pass it on - does not correspond to the idea in Sankt Walburg."
After her election as abbess in January 2019, she moved to Eichstätt from America.
"When I accepted the election, I underestimated the cultural differences involved in living up to expectations in a foreign country and in a foreign language."
Hanke: "I know that this decision was not easy for you"
The nun added that she had perceived her role as abbess of a monastic convent differently in her home monastery.
In Eichstätt, on the other hand, the abbess is a public figure with social relevance.
"The demands of the role are different to what I learnt in my convent training."
Eichstätt's Bishop Gregor Maria Hanke thanked Dubnick for her work: "I know that this decision was not easy for you. All the more reason for me to respect you for having the courage to take this path."
Hildegard Dubnick was born in Oak Park, Illinois, in 1961. She studied comparative linguistics and German.
The convent, which she joined in 1987, was founded by the Eichstätt abbess Maria Benedicta von Spiegel in 1935 as a daughter foundation of St Walburg Abbey.
Following her resignation on Palm Sunday, Dubnick will retire to another convent for some time out before returning to the United States later this year, according to a statement.
The Benedictine Abbey of St Walburg is historically significant in two ways.
Firstly, it guards the tomb of St Walburga, the patron saint of the Eichstätt diocese (probably 710-779).
Secondly, Benedictine nuns have lived here continuously since it was founded in 1035.
This constant presence has preserved numerous art treasures and archives on site.