The American Society for the Prevention of Cruelty to Animals (ASPCA) is a non-profit organization dedicated to preventing animal cruelty. Based in New York City since its inception in 1866, the organization's mission is "to provide effective means for the prevention of cruelty to animals throughout the United States."

Following the creation of the Royal Society for the Prevention of Cruelty to Animals (RSPCA) in the United Kingdom in 1824 (given Royal status in 1840), Henry Bergh founded the American Society for the Prevention of Cruelty to Animals on April 10, 1866, in New York City on the belief that "animals are entitled to kind and respectful treatment at the hands of humans, and must be protected under the law". It is the oldest animal welfare organization in the United States. On February 8, 1866, Bergh pleaded on behalf of animals at a meeting at Clinton Hall in New York City. Some of the issues he discussed were cockfighting and the horrors of slaughterhouses. After getting signatures for his "Declaration of the Rights of Animals," Bergh was given an official charter to incorporate the ASPCA on April 10, 1866. On April 19, 1866, the first anti-cruelty law was passed in NY since the founding of ASPCA, and the organization was granted the right to enforce anti-cruelty laws. In 1867, ASPCA operated its first ambulance for injured horses and began advocating for more humane treatment of animals such as horses, live pigeons, cats, and dogs. Early goals of ASPCA focused on efforts for horses and livestock, since at the time they were used for a number of activities.

In 1918, ASPCA veterinarians developed the use of anesthesia and as a result were able to work on a horse with a broken kneecap. In 1954, ASPCA hospitals added pathology and radiography laboratories and programs. In 1961, ASPCA veterinarians performed their first open-heart surgery on a dog.

From 1894 to 1994, the ASPCA operated the municipal animal shelter system in New York City which euthanized unadopted animals. Starting in 1977, the ASPCA entered into a contract with the New York City Department of Health to receive municipal funding to operate the shelter system. The contract rendered the ASPCA increasingly reliant on government income rather than private donations, and subject to the effects of annual city budget appropriations. In 1993, the ASPCA decided not to renew its contract for operating the shelter system. Operation of the shelter system was transferred to Center for Animal Care and Control, later renamed Animal Care Centers of NYC, in 1995.

In 1996, ASPCA acquired the Animal Poison Control Center from the University of Illinois. In 2013, the ASPCA made a $25 million commitment to assist at-risk animals and pet owners in the greater Los Angeles metropolitan area, including a fully subsidized spay/neuter facility in South Los Angeles operated by the ASPCA and a campaign to encourage the fostering of local vulnerable kittens.

In 2014, ASPCA spoke out in support of New York City's new mayor's (Bill de Blasio) campaign to ban horse-drawn carriages in the city.

In 2014, ASPCA opened the Gloria Gurney Canine Annex for Recovery & Enrichment (CARE) in NYC to house dogs brought by the NYPD to the ASPCA in connection with animal cruelty investigations. In 2014, ASPCA also opened the ASPCA Kitten Nursery in NYC to care for neonate and very young homeless kittens until they are appropriate for adoption.

In 2015, ASPCA acquired the Asheville, North Carolina–based Humane Alliance, now called the ASPCA Spay/Neuter Alliance.