The 48-year-old was seriously assaulted in Comely Bank at about 02:45. He was taken to Hairmyres Hospital, where he has undergone surgery for his injuries.
The two men who attacked him used weapons and attempted to conceal their identities.
Police have appealed for witnesses to the attack to come forward and have said they are trying to establish a motive.
The first suspect is described as between 5ft 8ins and 5ft 9ins tall, of slim build, wearing a dark hooded top, dark bottoms and dark shoes.
The second man is 5ft 6ins to 5ft 7ins, slim, wearing a dark hooded top, dark bottoms and light-coloured shoes.
Det Sgt Ronnie Douglas said: "We are in the process of piecing together the circumstances of what has happened. We need to establish the motive for this attack which has left a 48-year-old man seriously injured.
"I am appealing to people in the local community to contact us. Did you hear shouting or any kind of disturbance? Did you witness the attack? Or perhaps you saw the two suspects run off.
"If you have any information, even if you think it's not important, please pass it on to officers."
He added: "Additional officers will be patrolling the area to reassure members of the public. If anyone has any concerns then please speak to these officers."
Detectives have said an attack on a man in Hamilton was attempted murder.