Hughes had a chance to put her side ahead soon after the restart, looking to continue her fine goalscoring form as she turned and shot inside the box – but her effort flew just wide of the goal.
Soon after, Sharpe whipped a cross deep into the box which found Polly Doran at the back post; her shot was blocked and cleared off the line.
Youngsters Alexia Potter and Araya Dennis came off the bench on the 58th minute – and duly both made a massive impact on the game.
Potter put the side ahead for the first time of the afternoon on the 70th minute as she netted her first professional goal. The midfielder created some space inside the final third before blasting a strike from the edge of the box which found the bottom left-hand corner of goal.
Sharpe extended Palace’s lead 11 minutes later as she volleyed home a superb cross from Dennis at the back post.
Sharpe’s brilliant first-time goal proved to be the match-winner, as Blades pulled one back for Lewes deep into stoppage time to reduce Lewes' deficit.
But Palace clung on to take all three points and move up to third in the Women's Championship table, a point behind leaders Charlton – having played a game fewer.
Next up for the free-scoring Eagles: hosting fourth-placed Southampton at Selhurst Park next Sunday, 19th November (14:00 GMT kick-off), in front of what is already set to be a record crowd.
Palace: Lambourne (GK), Doran, Everett, Nolan, Cataldo, Arthur (Filbey, 74), Guyatt (Potter, 58), Hopcroft (Reilly, 90+2), Bailey-Gayle (Dennis, 58), Sharpe, Hughes
Subs: Negri, Gibbons, Johnson
Lewes: Whitehouse (GK), Hazard, Riglar, Garrard, Hamilton, Grey, Olding, Farrugia (Mooney, 74), Blades, Brasero-Carreira, Palmer
Subs: Moore, Cleverly, Hack, Pursey, Oakley