[10] Sisolak is a successful entrepreneur and was a partner in the American Distributing Company, a telemarketing venture that sells coffee cups, pens, and various other promotional items to businesses.

[11] Sisolak ran for the Nevada Senate in the Las Vegas-based 5th district in 1996, losing to Republican incumbent Ann O'Connell.

[11] During his time on the Board of Regents, Sisolak discovered that thousands of Nevada students had been wrongly charged out-of-state tuition and won refunds for them.

"[16] Sisolak fought to bring back a popular apprenticeship program at the College of Southern Nevada that was abruptly canceled during the recession.

[28] Sisolak won praise from the conservative Nevada Policy Research Institute for fighting against waste, fraud, and abuse.

[41] Sisolak is involved with many civic, charitable and business organizations, including the Henderson Chamber of Commerce, the American Red Cross-Clark County Chapter, the UNLV Alumni Association, Seniors United, American Red Cross Leadership Council, Las Vegas Chamber of Commerce, Las Vegas Better Business Bureau, the Boys & Girls Club, Hispanics in Politics, St. Joseph Husband of Mary Catholic Church, and the Nevada Partnership for Homeless Youth.

[49] He released a healthcare policy platform that included proposals to reduce pharmaceutical drug prices, fix Nevada's doctor shortage, and protect Nevadans with preexisting conditions.

On May 30, 2019, Sisolak vetoed a bill that proposed the adoption of National Popular Vote Interstate Compact in the presidential elections.

[64] On March 15, 2021, Sisolak, along with Vice President Kamala Harris and Second Gentleman Doug Emhoff, toured a UNLV vaccination site together.

Sisolak issued a statement which read "I want to thank Vice President Kamala Harris and Second Gentleman Doug Emhoff for coming to Nevada today to see the incredible work the State is doing – in partnership with leaders, volunteers and organizers at the local level – to administer the COVID-19 vaccines as fast as our federal allocation allows and ensure that all Nevadans who want access to the life-saving vaccines have access as soon as possible.

[67] Sisolak filled the vacancy on December 16, 2021, when he announced Las Vegas educator Lisa Cano Burkhead as Nevada's new lieutenant governor.

[80] Shortly after being elected governor in 2018, Sisolak announced his engagement to Kathy Ong, an Ely native and his girlfriend of five years.

[82][83] Sisolak, a property owner on Las Vegas Boulevard South, received a total of $23.5 million in 2005 after the "airport refused to pay him for height restrictions imposed on a parcel he owned".

[84] McCarran officials had warned that paying off property owners who lost land value because of the height restrictions could cost more than $1 billion and make air travel to or from Las Vegas more expensive.

Still, the Nevada Supreme Court ruled that landowners can seek compensation if planes flying below 500 feet hinder their ability to develop high-rise buildings.

[85][86] Sisolak has been accused by mining corporation Gypsum Resources LLC of engaging in a quid pro quo valued at $150 million during his time as Clark County commissioner chairman.

[87] Gypsum claims that at the end of Sisolak's term as chairman, while running for Nevada governor, he exchanged political favors with Save Red Rock attorney Justin Jones, who himself was campaigning for a seat on the Clark County commission.

[88] Save Red Rock, a nonprofit environmental activist group, has consistently expressed opposition toward Gypsum Resources LLC since its inception.

[90] Conversely, Clark County has attempted to bar Save Red Rock from raising concerns about Gypsum Resources' development projects at public hearings.

[91] This legal battle persisted until the end of 2018, when Save Red Rock suddenly dropped its lawsuit against Clark County.

Gypsum alleges that Jones and Sisolak engaged in covert dealings, with Jones agreeing to drop Save Red Rock's lawsuit and provide Sisolak's gubernatorial campaign with the support of environmentalist groups if the Clark County commission denied Gypsum Resources' final appeal to complete its proposed development in Red Rock.

[88] In Gypsum Resources' bankruptcy filing, it accuses the county of covering up “facts about governmental misconduct” relating to Jones's and Sisolak's covert deals.