Praveen Poojary (28) and Akshay Devadiga (20) were surrounded and attacked with sharp weapons by the VHP and Bajrang Dal activists as they were transporting three cows in a vehicle, Udupi district Superintendent of Police K T Balakrishna told PTI.
Poojary died instantly while Devadiga has been admitted to a hospital at Bramhavar, he said.
Seventeen people were arrested and a hunt was on to nab the others involved, he said.
The coastal districts of Udupi and Dakshina Kannada have been reporting cases of cow vigilantism in the last several years.
The incident comes days after the Union home ministry had cracked the whip on cow vigilantism, asking all states not to tolerate anyone taking law into their hands in the name of protecting cow and to take prompt action against such offenders.
The home ministry advisory had come two days after Prime Minister Narendra Modi attacked cow vigilantes and asked people to beware of these 'fake' protectors trying to divide the society and the country.
He made these comments after his government and BJP came under attack over incidents of violence against Dalits and Muslims by cow vigilantes in various states including Uttar Pradesh, Gujarat and Madhya Pradesh.
Meanwhile, Karnataka Home Minister G Parameshwara said prima facie cattle trade-related business dispute may be the reason behind the killing of the BJP worker.
"... Seventeen people have been arrested in connection with the incident, they (police) are suspecting some sort of a cattle trade-related business dispute," he told reporters in Bengaluru, adding police have taken up the case.
Noting that he does not see a communal angle to the incident "at this point of time", Parameshwara said "some reason must be there, we will find out".
He said "... We don't know at this stage, but they are suspecting some sort of a dispute because of the trade, it is not definite, but they are suspecting. Investigation will give us the final picture."
Parameshwara also expressed concern over repeated incidents relating to beef and cattle trade in Karnataka.
"We are vigilant, we will definitely try and maintain peace and order. I appeal to the people who are trying to create this kind of disturbance not to do this because we are a tolerant society and we should not create these kind of issues," he said.