The roadblocks for the planar silver/silver chloride (Ag/AgCl) quasi-reference electrode (qRE) development are the potential stability and long-term reliability as potentiometric sensors. Although there is a significant amount of work on potentiometric screen-printed and inkjet-printed sensors, none of the REs has comparable performance to that of the conventional glass RE and knowledge on reliable planar Ag/AgCl qREs is still limited. Here, a novel fishbone-structured flexible Ag/AgCl qRE (Fishbone-Ag/AgCl qRE) was developed and its stability and long-term reliability were significantly improved. The stability of the Fishbone-Ag/AgCl qRE was comparable to that of a commercial glass Ag/AgCl RE. In a long-term stability test, the Fishbone-Ag/AgCl qRE could continuously and stably operate for more than 4 h. Shelf-life testing revealed a 6 month life span. The conductivity and diameter of the nanowires in the fishbone structure of the Ag/AgCl qRE had important influences on electrochemical properties. The conductivity of the qRE influenced the charge-transfer rate in the electrode so that it affected the potential stability. Thicker diameter and slight chlorination on the surface of the AgNWs resulted in enhanced long-term reliability of the qRE. The capabilities of this new nanostructured material were applied in vivo for noninvasive monitoring of electrocardiogram. The discovery is elementary and substantially informs improved nanostructure RE design for testing and commercial medical device applications.