Serpent of Time takes place at Hikone Castle on Lake Biwa, in the port cities of Sakai and Kishiwada, the town of Kudoyama, and in and around Mt. Kôya.
During Japan's medieval period, Sakai was a wealthy city-state and a thriving international port. Kishiwada is ten miles south of Sakai.
I charted Ryô's escapes from Sakai (turning inland at Kishiwada) and Mt. Kôya using Meiji Era maps of Ôsaka and Wakayama published online by the East Asia Library at the University of California, Berkeley.
The crossroads town of Hidaka (now Katsuragi township) on the West Kôya highway (not be confused with Hidaka District, south of Wakayama City) is home to the Katsuragi Mishima hot springs resort.
As Ryô discovers, the road from Mt. Kôya now follows the Fudôtani and Nyû Rivers. Yoshino, the seat of the Southern Court, is today a small resort town twenty miles east of Kudoyama in Nara Prefecture (then Yamato Province).
The distances described in the story, however, are not necessarily to scale, and have been expanded in some places and condensed in others to accommodate the plot.
A Google "street view" is available for the route Ishibashi-san takes from Kii Kamiya to Kudoyama (click on the map for the interactive format).
Kudoyama's most famous resident was Sanada Yukimura. Allies of Ishida Mitsunari and foes of Tokugawa Ieyasu, Yukimura and his father were exiled to Kudoyama after Mitsunari's defeat at the Battle of Sekigahara in 1600.
Yukimura again faced off against the Tokugawa regime during the Siege of Ôsaka (1614–1615) and died heroically (impressing even his enemies) during the castle's last stand.
Mt. Kôya is accessible from Ôsaka via the Nankai Kôya Line. The train ride itself is a fascinating journey from the megalopolis to the countryside. Nankai Kôya Hot Net is a good resource for day trippers and overnight travelers.