Shiro Sanada serves as chief science officer aboard the Yamato within the original series continuity, including Final Yamato. His limbs are bionic prosthetics, the consequence of a childhood accident that also claimed his sister's life, leading to a period of resentment toward scientific overreach. Sanada studied alongside Mamoru Kodai at the National Space Defense Academy, forming a friendship. He later blamed himself for Mamoru's presumed death, believing he inadequately repaired the destroyer Yukikaze before its final battle, reflecting a persistent sense of responsibility for perceived failures.

Onboard the Yamato, Sanada provides critical technical expertise and analytical problem-solving during missions. He frequently advises acting captain Susumu Kodai, serving as a level-headed and mature counterbalance during crises. Following Captain Okita's death and Engineer Tokugawa's passing, Sanada becomes one of the senior spokespersons for the crew. His leadership extends beyond technical matters; he demonstrates calmness under pressure and maintains privacy regarding his personal emotions while offering guidance to younger officers.

After Final Yamato, Sanada transitions into higher command roles within the Earth Defense Forces. By 2202, during the black hole crisis in Resurrection, he holds the position of Director of the Space Science Bureau. In this capacity, he oversees Earth's desperate emigration plan, coordinating the scientific response to the Cascade Black Hole threat. He personally appoints Yuki Mori Kodai to lead the First Emigration Fleet. When the Third Fleet requires command, Sanada recruits Susumu Kodai to captain the rebuilt Yamato, entrusting him with the vessel's operations while retaining oversight of the broader mission.

Later, Sanada assumes direct command of the modified Dreadnought-class Battlecarrier Hyuga during the 65th Escort Corps' peace mission to the Salezar system. This assignment places him in operational command during the Iscandar Incident, where he engages Dezariam's forces. Following this conflict, he faces dismissal but is subsequently reassigned to the Yamato at the Icarus Observatory for the classified Operation DAD. During this operation, he heads the observation team for Sasha Iscandar Kodai, the hybrid daughter of his deceased friend Mamoru Kodai, indicating ongoing protective responsibilities tied to personal history. After combat at the observatory, Sanada resumes his post as Executive Officer aboard Yamato for its subsequent mission toward Dezariam's homeland.