Speaking to reporters before arriving in Tokyo on a trip to Asia, Mr Panetta appealed for restraint amid mounting tensions over territorial rights in the East China Sea and the South China Sea.
"I am concerned that when these countries engage in provocations of one kind or another over these various islands, that it raises the possibility that a misjudgment on one side or the other could result in violence, and could result in conflict," Mr Panetta said, when asked about a clash between Japan and China.
"And that conflict would then have the potential of expanding."
The Pentagon chief's trip coincides with an escalating row between Asia's two largest economies over an archipelago in the East China Sea administered by Tokyo under the name Senkaku and claimed by China under the name Diaoyu.
Tensions have steadily mounted since pro-Beijing activists were arrested and deported after landing on one of the islands in August. Japanese nationalists then followed, raising their flag on the same island days later.
On Tuesday, Japan announced it had nationalised three of the islands in the chain, triggering protests in China. Tokyo already owns another and leases the fifth.
The uninhabited islands are in important sea lanes and the seabed nearby is thought to harbour valuable mineral resources.
Sometimes violent demonstrations have been held in China near diplomatic missions in the days since Tokyo's announcement, although there have been no reports of deaths or serious injuries.
Hong Kong broadcaster Cable TV showed footage of clashes on Sunday in Shenzhen between riot police and demonstrators, with some holding a banner calling for a "bloodbath" in Tokyo.
Mr Panetta is due to hold talks on Monday with his Japanese counterpart, where the dispute is expected to top the agenda, before heading to China, then New Zealand.
Territorial disputes in the South China Sea also have Washington worried, as China has refused to withdraw claims to virtually all of the strategic waterway and has been accused of bullying smaller states in the area.
The Philippines and Vietnam have alleged Beijing has used intimidation to push its claims in the South China Sea, through which about half of the world's cargo passes.