The incorporators of HSUS included four people—Larry Andrews, Marcia Glaser, Helen Jones, and Fred Myers—all of whom were active in the leadership of existing local and national groups, who would become its first four employees.

HSUS's guiding principle was ratified by its national membership in 1956: "The Humane Society of the United States opposes and seeks to prevent all use or exploitation of animals that causes pain, suffering, or fear.

The development of sympathy for creatures in pain, the satisfaction of keeping them as pets, and the heightening awareness about the relationship between cruelty to animals and interpersonal violence strengthened the movement's popular appeal.

"[18] Myers and his colleagues found another exemplar of their values in Joseph Wood Krutch (1893–1970), whose writings reflected a deep level of appreciation for wilderness and for nonhuman life.

His principal concern, like that of HSUS, was the mitigation and elimination of suffering, and he endorsed the view that ethical treatment sometimes permitted or even required killing animals to end their misery.

"[3] Beginning in the 1990s, HSUS board member David O. Wiebers, a medical doctor associated with the Mayo Clinic, undertook efforts to lessen tensions between animal protection organizations and the scientific community, and to seek to identify areas of common agreement.

[26] Service to local animal shelters, with a special focus on solving problems and challenges of importance to every one of the nation's humane societies, was an early priority for HSUS.

Under Phyllis Wright, HSUS was a driving force behind the shift to use of sodium pentobarbital for animal euthanasia, in opposition to the use of gas chambers and decompression, the standard shelter killing methods until the early 1980s.

[31] In 1961, HSUS investigator Frank McMahon launched a probe of dog dealers around the country to generate support for a federal law to prevent cruelty to animals destined for use in laboratories.

[32][33] The Life spread sparked outrage, and tens of thousands of Americans wrote to their congressional representatives, demanding action to protect animals and prevent pet theft.

[53] Since Pacelle's appointment, HSUS has claimed successes such as the adoption of "cage-free" egg-purchasing policies by hundreds of universities and dozens of corporations;[54] the exposure of an international trophy hunting scam subsequently ended through legislative reform;[55] a number of successful congressional votes to outlaw horse slaughter; progress in securing legislation at the state and federal level to outlaw animal fighting and the interstate transport of fighting implements;[56] the enactment of internet hunting bans in nearly all of the states;[57] announcements by Wolfgang Puck and Burger King that they would increase their use of animal products derived under less abusive standards;[58] and an agreement by the U.S. Department of Agriculture to begin enforcement of federal laws concerning the transportation of farm animals.

[59] In 2018, The Washington Post reported on a Humane Society board investigation conducted by Morgan, Lewis & Bockius into allegations of sexual harassment involving Wayne Pacelle.

In 2010, the section estimated that it had filed more than 50 legal actions in 25 states, and won 80% of its cases, while booking 10,000 hours of pro bono attorney time for a total in-kind contribution of $4 million.

The program provides speakers, produces videos and other materials, and works with faith leaders to lead discussion of animal issues within the broader religious community.

HSISP has held three conferences, the first on purebred dogs and genetic defects, the second on outdoor cats and associated management issues, and the third on sentience as a factor in determining animal welfare policy.

[90] In February 2008, after an undercover investigation conducted by HSUS at the Westland Meat Packing Company alleged substantial animal abuse, the USDA forced the recall of 143 million pounds of beef, some of which had been routed into the nation's school lunch program.

The measure, which prohibits certain intensive confinement practices in agriculture beginning in 2015, passed by a 63.3 to 36.7 percent margin, winning in 46 of 58 counties, and gaining support throughout the state's urban, suburban, and rural areas.

Additional negotiations produced the agreement to pursue federal legislation, the Egg Products Inspection Act of 2013, to support a shift to cage-free housing systems for laying hens, like enriched colony cages.

Hog producers in particular recognized their vulnerability in reference to gestation crates[112][113][114][115] In July 2007, HSUS led calls for the National Football League to suspend Atlanta Falcons quarterback Michael Vick in the wake of allegations that he had been involved with dog fighting activity.

[118][119] Beginning in the 1990s, HSUS board member David O. Wiebers, a medical doctor associated with the Mayo Clinic, undertook efforts to lessen tensions between animal protection organizations and the scientific community, and to seek to identify areas of common agreement.

[164][165] The HSUS also heavily lobbied for the passing of HB 4393 in West Virginia,[166] which generated a large amount of controversy when its restricted animal list was originally drafted and made illegal the private ownership of common and harmless exotic pets, such as hamsters, hedgehogs, turtles, tortoises, pufferfish, sugar gliders, salamanders, alpacas and domestic hybrid cat breeds.

[128] According to its IRS Form 990, HSUS makes grants to organizations that meet its mission criteria, and typically to those groups which it has researched, with which it has an existing relationship, or with which its staff members have interacted at events and through other channels.

HSWLT has taken both large and small properties under its protection, through title donations, conservation easements, and formal agreements, to provide sanctuaries for a variety of animal species.

"[204] In the summer of 2014, the United States Fish and Wildlife Service reopened its admission of comments on whether to list the five remaining species of snakes on the Lacey Act, including boa constrictors.

[210] In 2006, the Attorney General of Louisiana opened an inquiry into the American Red Cross and HSUS after complaints about the misuse of funds raised in the aftermath of Hurricane Katrina.

This litigation was dismissed in 2009, with the judge finding that animal-rights groups had paid the key witness, a former Feld employee, at least $190,000, a significant amount of which was in a check signed by Mr. Pacelle.

[232] More recently, the debate over forcing animal welfare organizations to release information about cruelty within a specified period of time has prompted criticism from editorial boards and journalists skeptical of the motivations for such calls.

[233] The football player Michael Vick was sentenced to prison for running a dogfighting ring; he was found to have buried dogs alive, drowned them, beaten them to death, and pulled out their teeth without anesthetic.

[244] Animal fighting experts generally agree that since the Vick case, there has been a significant strengthening of anti-cruelty laws at the state level, making it easier to prosecute wrongdoers.

[259] In their November 2016 review of the HSUS Farm Animal Protection Campaign, ACE cited their strengths as their large reach, strategic approach, and long track record of legal work, corporate outreach, and meat reduction programs.