From Syria to the Boston bombings, missile defense, Iran and North Korea and rows over a ban on American adoptions of Russian children and the shuttering of US aid agencies, the litany of troubles awaiting resolution is huge.
"Too much to frontload the agenda with when he gets there," agreed Russia expert Fiona Hill, director of the Center on the United States and Europe at the Brookings Institution.
While Kerry knows many of the Russian leadership from his days as a senator, this is his first trip to Moscow since taking up his post in February.
US-Russian ties - famously reset with an embarrassing photo-op under Kerry's predecessor Hillary Clinton when she and Foreign Minister Sergei Lavrov pushed a mock red button - have plunged to new lows since Vladimir Putin's return to presidency in May 2012.
Analysts cautioned little concrete progress is likely to emerge, although there were expectations Kerry would meet Tuesday with Putin, in a rare break with diplomatic protocol by Moscow.
"Obviously one of the main points of the trip is to try to take the edge off all of the rhetoric, and try to find some way of figuring out if there are some concrete areas where we can go forward," Hill said.
"If there's just a glimmer that they are in the mood, at least for now, to try to put things on a more cordial level, that in itself would be an achievement."
The timing of the two-day visit is also key, coming after last month's carnage at the Boston marathon, blamed on two brothers of Chechen descent, and as the US says it fears chemical weapons may have been used in Syria.
Kerry will seek to loosen Moscow's stubbornly strong ties to the regime of Syrian President Bashar al-Assad by sharing US fears of Syria's use of chemical weapons -- an avowed "red line" by both sides.
Increased US talk that the administration of President Barack Obama may consider arming the rebels may also be designed to pressure Moscow to use its sway over Assad to stop the bloodshed.
However, "I don't think the Russians will make any compromise," Hill said.
"The Russians have no interest whatsoever in dealing with the opposition. They don't see any perspective for stability or any kind of solution to emerge out of arming the opposition."
"Moscow is not in favor of more death and violence," agreed expert Matthew Rojansky, "they are simply concerned that the next step is going to be an Islamist regime that no-one can contain."
Kerry will also be preparing the way for talks expected in Northern Ireland next month between President Barack Obama and Putin on the sidelines of the G8 summit, with the US leader also searching for more bilateral nuclear arms cuts.
Despite their tense ties, the two nations have managed to collaborate on the issue of Iran and North Korea's suspect nuclear programs.
And Rojansky, deputy director for the Russia and Eurasia program at the Carnegie Endowment for International Peace, said, particularly after the Boston attacks, such high-level interaction was "positive."
"They need to have a discussion to satisfy the Russians that, 'No we are not blaming this whole thing against you,'" he said, arguing for better security cooperation between the two former Cold War foes.
Moscow is likely to fear "the US is now warming up to some kind of crusade against Russia as the enabler of some kind of global post-Soviet terrorism," he said, after it emerged that one of the Tsarnaev brothers had been in the sights of the Russian authorities as early as 2011.
"God forbid for both sides, that something should come out in the press indicating that the Russians knew more than they let on," Rojansky said.
"If the Russians knew something that could have saved American lives and they didn't share it, it's going to be a crisis for the relationship."
For its part, Moscow will want to probe the top US diplomat about a recent US decision to abandon the final phase of its missile shield for Europe in favor of deploying new interceptors against a possible attack from North Korea.
Late last year, Moscow kicked out the US development agency USAID, and then banned Americans from adopting Russian children after Washington agreed a law targeting Russian officials suspected of human rights abuses.
Putin is unlikely to budge on either of those issues, experts believe.