Syrian state radio proclaimed Wednesday Assad's forces had taken Qusair after a night-time assault spearheaded by Hezbollah fighters.
Rebel officials conceded their rearguard had escaped through a gap in the attackers' lines.
The victory at Qusair, 6 miles east of Lebanon in Syria's Homs province, comes amid a series of offensives by Assad's forces and will boost morale among the regime's troops, which rebel source say include Iranian Revolutionary Guards as well as Hezbollah brigades.
It will also encourage Assad "to stay the course and crush the rebellion," noted U.S. military analyst Jeffrey White, a former military intelligence officer.
"As a result the regime will be even less likely to negotiate a true transition of power, deflating the hopes of those pressing for a diplomatic solution.
"A regime that has shown no inclination to negotiate while losing the war will hardly be moved to compromise if it believes its prospects have improved," White observed in an analysis for the Washington Institute for Near East Policy.
Taking Qusair after 17 days of heavy fighting restores the Damascus regime's control of the highway to Aleppo, Syria's commercial heart and second city, which already looks like Assad's next target.
The Free Syrian Army, the main rebel force, said Tuesday 4,000 Hezbollah fighters reached Aleppo, half of which has been under rebel control since 2012.
But most critically Qusair re-establishes Assad's access to the heartland of his minority Alawite sect on the northwestern Mediterranean coast.
On the rebel side, the loss of Qusair, which the insurgents had held for more than a year to secure untrammeled access to supply routes from Lebanon, is a serious setback.
The rebels were heavily outgunned and outnumbered throughout the siege.
The fall of Qusair, though likely to heighten the differences among disparate elements of the rebel group, could spur Western nations to provide arms in considerable quantities to the rebels to block further advances by Assad's forces.
Despite all this, analyst David Gardner in Beirut says the development "is not ... a turning point in the war. Rather, it cements a stalemate that, until now, had been dynamic.
"The combined forces loyal to the Assads still cannot regain control of large, mostly rural swathes of Syria, while rebel forces are still too fragmented, ideologically divided and poorly armed to depose the regime."
The regime's gains, Hezbollah's critical role in retaking Qusair and within Assad's reorganized forces, also spell trouble for Lebanon.
The Syrian war, now into its third year, is seriously aggravating sectarian rivalries between the Shiites, the largest single sect in Lebanon, and the Sunnis, aided by their coreligionists in Sunni-majority Syria.
The largely secular FSA and the jihadist al-Nusra Front have both threatened to strike Hezbollah where it lives for helping keep Assad in power.
Indeed, 10 days ago in Dahiyeh, Hezbollah's stronghold and presumed command center in southern Beirut, was hit by a couple of rockets fired from nearby hills.
They did little damage, but it was the first time Dahiyeh had been hit since Israeli airstrikes during the 2006 war, and the message was crystal clear.
On Saturday, Hezbollah's heartland in the Bekaa Valley in northeast Lebanon, was blasted by rocket and mortar fire from Syria.
Hezbollah retaliated, ambushing a Syrian rebel group, killing a dozen fighters in the first such action on Lebanese soil.
Fighting between Sunni militants and Alawite militiamen in the northern port of Tripoli has raged for two weeks, leaving 30 dead and scores wounded.
Anti-Hezbollah Sunnis led by militant clerics are staging rowdy protests against the Shiite movement in the southern port of Sidon.
Hezbollah has been infiltrating that Sunni bastion, where the opening shots of Lebanon's 1975-90 civil war were fired, in recent months.
If Sidon erupts, the bloodletting will swiftly spread to Beirut, a half-hour's drive north on the coastal highway.
"Reprisals inside Lebanon, by either Syrian rebel forces or their Sunni sympathizers and aimed at Hezbollah and its allies, are now a near certainty," Gardner wrote in The Financial Times.
2014: The Year in Music [PHOTOS]