Gus Poyet's in-form side handed Sheffield Wednesday a sound beating after taking a first-half lead through Wayne Bridge's deflected free-kick.
But there was nothing fortuitous about the way they tore through their opponents at the start of the second half.
Mackail-Smith followed up consecutive braces against Barnsley and Burnley with a simple 54th minute finish following a jinking run from Spanish full-back Bruno Saltor.
Will Buckley made it three shortly afterward, with Bruno once again the architect, as Brighton secured a third consecutive win.
Dave Jones' Wednesday have now suffered back-to-back losses to check their impressive start.
On-loan Southampton midfielder Dean Hammond made his second Brighton debut in place of hamstring injury victim Andrew Crofts, while Buckley returned from a hip problem to make a first start this season and push Kazenga LuaLua to the substitutes' bench.
Joe Mattock, who enjoyed a spell at the Amex Stadium last season, came into Wednesday's defence due to Lewis Buxton's hamstring strain and QPR loanee Jay Bothroyd was handed a debut in attack, with new recruit Ross Barkley named on the bench.
Buckley forced a sharp stop from Wednesday goalkeeper Chris Kirkland at the end of a 15th-minute counter-attack he instigated when a pass to the unmarked Mackail-Smith might have been the better option.
The visitors weathered some pressure immediately after this chance but fell behind in the 24th minute. Bridge initially fainted to strike the dead ball from the edge of the area and, with the Wednesday wall attempting to reorganise, he hit a shot that looped off Rhys McCabe and beyond Kirkland into the far corner.
Bruno unconvincingly cleared McCabe's cross as Wednesday sought a response - something that looked most likely when the lively Jermaine Johnson was in possession.
Five minutes before half-time, Buckley's surge at the Owls defence forced Mattock to clear his low centre from the goalmouth.
On-loan Everton youngster Barkley was introduced in place of Rodri at the interval as Jones sought a spark, only for Brighton to double their lead nine minutes into the second period.
Bruno wormed his way through challenges to get inside the box from the right and his low cross allowed Mackail-Smith to stroke home.
Albion goalkeeper Tomasz Kuszczak was scrambling as a curling Johnson effort flashed narrowly wide - a brief respite before Brighton made the points safe in sumptuous fashion.
Bruno's lofted diagonal ball caught out Wednesday's defence and found the rampaging Buckley, whose excellent first touch set up a cool, chipped finish.
It was almost four with an hour gone when Kirkland produced a superb reaction save from Mackail-Smith's header.
Wednesday belatedly tested Kuszczak inside the last 15 minutes - the first stop displaying excellent reflexes to thwart Bothroyd's close range header before Mattock's stinging drive was touched to safety.