The notorious 77-year-old strongman, who has ruled Uzbekistan for a quarter century since its independence, met Kerry at the airport in thick fog.
The leaders then headed into the city to a conference centre in the sprawling grounds of the monumental presidential residence complex for closed-door talks.
According to the US State Department’s own 2014 human rights report, Uzbekistan’s electoral system is rigged and torture and corruption run rampant.
In more colourful language, a leaked 2010 US diplomatic cable published by WikiLeaks branded Karimov’s realm “a nightmarish world of rampant corruption, organised crime, forced labour in the cotton fields and torture.”
Kerry, who on Saturday had a difficult discussion on human rights with his Kyrgyz counterpart, has said he will not shy away from criticising his hosts on his tour.
But he has also made it clear that Washington is ready to maintain and improve its diplomatic ties in the region despite its concerns.
Samarkand, an ancient centre of Islamic learning, was to be the backdrop to the first ministers’ meeting between the United States and all five Central Asian powers.
Diplomats hope the new format bearing the less than exotic name of “C5+1” will become an ongoing forum for cooperation between Washington and the “‘Stans”.
Kerry and the foreign ministers from Kyrgyzstan, Uzbekistan, Kazakhstan, Tajikistan and Turkmenistan met and ate a working lunch before visiting the historic city.
Washington was among the first foreign capitals to recognise the independence of the Central Asian republics a quarter-century ago when the Soviet Union collapsed.
Since then, Central Asia has tried to maintain a balance between its relations with former master Moscow, rising economic partner China and the United States.
At the height of hostilities in neighbouring Afghanistan, NATO’s war machine maintained important logistics centres in the region, but these have now been closed.
Instead, a newly assertive Russia and a China keen to invest in trade and infrastructure have gained diplomatic ground, with the United States somewhat on the sidelines.
But US and Central Asian officials argue the republics’ relationship with Washington gives them leverage to assert their own agenda in the face of their bigger neighbours.
Kerry is part-way through his first tour of all five of the countries, and has come promising investment in education and cooperation on security threats.