The Scotland international striker opened the scoring in the 13th minute on Tuesday night with a fantastic finish into the top corner - his first goal in 10 league games.
Mackail-Smith also hit a post in the closing stages but his strike was enough to help the Seagulls win at Derby for the first time in 27 years.
It also earned Guy Poyet's side a third victory in four games, with the south coast club having goalkeeper Casper Ankergren to thank too for making several fine first half saves.
Tamas Priskin, on loan from Ipswich, marked his debut with the opening goal in Saturday's 3-1 defeat to West Ham at Upton Park.
The Hungarian nearly did the same within a minute on his home bow but his right-footed strike went wide from 18 yards.
In a flying start, Will Hoskin, recalled to the Brighton side, then had his 18-yard effort comfortably saved by Rams goalkeeper Frank Fielding.
The Rams, with just one victory in their last 10 league matches, made a decent start and forced Seagulls keeper Ankergren into action, with the Dane keeping out Craig Bryson's 25-yard effort.
But the visitors opened the scoring in the 13th minute, with Mackail-Smith finishing into the top corner from a cross by Inigo Calderon.
Derby produced an excellent response and twice came close to pulling level.
First, Priskin nearly took advantage of a slip in the Seagulls defence but Lewis Dunk got back to hack the ball clear before the returning Jeff Hendrick saw his 25-yard shot parried to safety by Ankergren.
Hendrick was impressing on his recall and fired another effort, this time failing to find the target from the edge of the area.
Still the home side made all the running and, after James Bailey shot wide, Ankergren was again called into action, this time keeping out Jamie Ward's long-range strike.
Brighton finished the first half on top and Gordon Greer flashed a shot over the bar from 18 yards following a corner.
It was a quiet start to the second half and it was not until the 62nd minute that Seagulls substitute Craig Noone blasting a shot wide from 18 yards.
Seven minutes later the lively Noone tried his luck again but with the same result.
Derby were doing their best to get themselves back on level terms and defender Jason Shackell saw his header from a Ward corner sail over the bar.
Mackail-Smith came close to wrapping up the points 11 minutes from time when his header from Noone's cross hit a post, with Hoskins driving the rebound wide.
Fifteen-year-old substitute Mason Bennett almost snatched an equaliser for the Rams but lifted his shot over the bar and despite late home pressure, the Seagulls survived.