The animal welfare charity outlined its concerns in a document sent to the local authority considering the planning application.
If approved, the £50m super dairy will be home to 8100 cows, producing 250,000 litres of milk daily and employing 85 staff.
Milking could begin as soon as this autumn at the Nocton Dairies farm, with cows housed largely indoors a few miles south of Lincoln.
A large farm in itself did not automatically mean that welfare would be compromised, acknowledged an RSPCA spokeswoman.
"It depends on a number of factors, such as the ratio of skilled staff to animals and the quality of the facilities," she added.
But an 8000-cow dairy herd raised ethical questions about whether animals were being viewed more as commodities than living creatures.
"The RSPCA does also have some very strong concerns about this particular proposal - such as the fact that there is an intention to milk the cows three times a day.
"We have already contacted the local planning authority with our thoughts, but until a decision is made we are unable to act further."
One in four UK dairy cows are lame at any one time, according to RSPCA figures. Up to 30% suffer from mastitis due to intensive milking, it claims.
"Many more dairy cows are culled for mastitis and lameness than bovine tuberculosis," said the spokeswoman.
But the NFU said the Nocton Dairies farm would be a showcase for animal welfare, cow management and modern milking technologies.
NFU chief dairy adviser Hayley Campbell-Gibbons said: "The welfare of the dairy cow is of fundamental importance on all British dairy farms."
The sector had changed a lot over the past 20 years as farmers took advantage of new technologies in breeding, milking and farming systems.
"This progress is not something to be fearful of; it means that we are constantly finding new and better ways to manage our cows."
It was also important to remember that housed systems pose no risk to the health and welfare of the animals involved, said Ms Campbell-Gibbons.
"British farmers adhere to world-leading standards of stockmanship, hygiene and animal welfare," she added.
Nocton Dairies said cow health was of the utmost importance. The dairy had been designed to deliver unparalleled animal welfare standards.
A vet would be on site 24 hours a day to support trained dairy staff in daily inspections to ensure all cows were healthy and happy.
In the event of a cow becoming ill, the unit would feature a dedicated "hospital" unit so they can be cared for to the highest standard.