The spirit of historical initiative serves as the driving force behind the Communist Party of China’s cultural mission in the new era. Under the guidance of this spirit, the Party’s century-long journey in fulfilling its cultural responsibilities has profoundly addressed key theoretical and practical questions regarding “who should take on,” “what should be undertaken,” and “how to fulfill”. Guided by Marxism, the Communist Party of China has consistently forged cultural subjectivity through historical confidence and self-awareness, laying a solid foundation for carrying out its cultural mission. Over the past hundred years, the Party has demonstrated the spirit of historical initiative, actively mastering the course of history and successively advancing culturally coherent missions—such as “building a new culture for the Chinese nation,” “modernizing science and culture,” “constructing socialist spiritual civilization,” and “continuing to promote cultural prosperity and building a strong cultural nation.” These reflect the Party’s continuous practice of seizing historical initiative and strengthening cultural self-awareness in the cultural domain. To fulfill the cultural mission of the new era, it is essential to accurately grasp the direction of history, continuously strengthen the Party’s leadership in culture; uphold historical confidence, consolidate cultural subjectivity, and advance independent and self-reliant cultural development; enhance historical initiative and deeply understand the laws governing cultural construction under the “two integrations”; and adhere to a people-centered value orientation in cultural development to achieve great historic accomplishments. A systematic examination of the guiding role of the spirit of historical initiative across the dimensions of subject, history, and practice fully confirms that this spirit is the key to the Party’s fulfillment of its cultural mission. Therefore, this spirit must be vigorously promoted on the new journey to provide strong cultural support for realizing the grand goals of socialist modernization and national rejuvenation.