Since 9/11, Uzbekistan has been at times critical to US foreign policy objectives in Central and South Asia, including in Afghanistan and in efforts to curb Russian influence in the region. Here's a look at some of the key ways Karimov's death could affect the US.
A onetime Soviet official, Karimov had led Uzbekistan since before that country's independence from the Soviet Union in 1991, making him one of the longest-serving rulers in the world.
After achieving statehood, Uzbekistan wanted independence from Russia and sought out relationships with the West. But there was "a certain level of disinterest" on the part of the US, Olga Oliker, the director of the Russia and Eurasia Program at the Center for Strategic and International Studies, told CNN.
It wasn't until the 9/11 terror attacks, when Washington was trying to gain the cooperation of countries near Afghanistan during its fight against al Qaeda and the Taliban, that US-Uzbekistan relations became an important element of American foreign policy.
Karimov backed the US-led intervention in Afghanistan, as he also saw the Taliban and al Qaeda as Uzbekistan's enemies. He previously backed the Northern Alliance, which had fought the Taliban during the 1990s and were key allies in the US operation to oust the Taliban.
Karimov let US forces use Uzbekistan's airspace and Karshi-Khanabad airbase to support operations in Afghanistan, with which it shares an 85-mile-long border.
But in 2005, Karimov kicked the US personnel out after the George W. Bush administration condemned a violent crackdown by Uzbek security forces against protesters in the city of Andijan. The State Department's 2015 human rights report on Uzbekistan said security officials reportedly killed "at least 187 unarmed civilians" in an event that has been described as the biggest attack on demonstrators since Tiananmen Square in 1989.
Despite the closure of the base, Karimov allowed the US to move equipment through Uzbekistan, which enabled the US to avoid the more problematic Pakistan-to-Afghanistan supply route.
During Karimov's reign, Uzbekistan faced a series of terrorist threats, most prominently the Islamic Movement of Uzbekistan (IMU). The US designated the IMU a foreign terrorist group in 2000 and the organization has since allied itself with al Qaeda and the Afghan and Pakistani Taliban.
Although the IMU carried out a series of car bombs in the Uzbek capital of Tashkent in 1999, the group has largely been confined to the Afghanistan-Pakistan border region.
But any instability in the wake of Karimov's death could leave a vacuum to be exploited by the IMU, which, according to the State Department, seeks to overthrow the Uzbek government and has declared allegiance to ISIS.
Approximately 500 citizens from Uzbekistan have traveled to Iraq and Syria as foreign fighters, according to the Soufan Group, a security consultancy. A citizen of Uzbekistan was one of the terrorists that carried out the June ISIS-linked attack
on the Istanbul international airport that killed more than 40 people.
The former US Ambassador to Uzbekistan, John Herbst, believes groups such as IMU will attempt to exploit the transition but doubts they'll be successful. He called Uzbekistan's security services the best in Central Asia.
Some analysts believe Karimov exaggerated the threat of terrorism, using it as an excuse to crack down on the opposition and maintain his authoritarian regime.
"The government used security concerns related to terrorism as a pretext for the detention of suspects, and potentially used it to prosecute religious activists and political dissidents," according to a State Department report.
Uzbekistan is often seen as one of the more independent former Soviet states in Central Asia. Some countries in the region have opted to join Russian-led organizations and would-be rivals to the European Union and NATO, such as the Eurasian Economic Union and Collective Security Treaty organization. Uzbekistan is not a member of either, even as Russia maintains military installations in three of Uzbekistan's neighbors: Kazakhstan, Tajikistan and Kyrgyzstan.
Karimov "wanted to make sure the Russians didn't get too much influence in the region," Oliker told CNN.
Herbst agreed, noting that unlike many of its neighbors, Uzbekistan was able to purge Russian agents from its military and security institutions, which helped cement its independence.
Oliker said Russian President Vladimir Putin is likely hoping that a more pro-Russian leader comes to power, saying it was possible that a new Uzbek leader with limited support might seek Moscow's backing as Russia "will have no qualms" about supporting a leader who participates in crackdowns.
Putin was quick to offer his condolences to Uzbekistan upon learning of Karimov's death.
"It is difficult to overestimate the contribution of Islam Karimov to the establishment of relations of strategic partnership between our countries," Putin said via a statement published on the Kremlin's website.
"There's no question Moscow would like a much closer relationship with Uzbekistan than it (had) under Karimov," Herbst said.
But he assessed, "There's a good chance" that Karimov's successor continues the same independent policies, noting that most Uzbek elites share Karimov's views.
Oliker also thinks the situation is likely to be relatively calm in the immediate future as Karimov's health has been poor for some time and a transition plan is likely in place.
She said it's even possible that a new leader might liberalize the economy and other elements of society in a bid to attract Western investment and support. Uzbekistan's economy is heavily dependent on energy and cotton exports, as well as remittances from millions of workers abroad in places like Russia.
As the most populous of the former Soviet states in Central Asia, Uzbekistan has long sought to be the region's leader and maintain its autonomy, a course of action likely to continue for the time being, despite the death of the only independent ruler the country has ever known.
"We have always had differences on human rights. I don't think those are going away," Herbst said, before adding that the US is interested in a stable, secure and geopolitically independent Uzbekistan,
China in recent years has also increased its presence in Central Asia with major investments in infrastructure and energy, and while Karimov welcomed the money, he kept the Chinese at arm's length.
"He was suspicious of everybody," Herbst said.