Antonio Candreva scored his ninth goal of the campaign to put the Biancoceleste ahead in the 42nd minute.
Despite playing in numerical inferiority following the sending off of midfielder Lucas Biglia for a second yellow card early in the second half, Lazio doubled their lead through Senad Lulic in the 73rd minute.
The outcome in Rome halted Sampdoria's three-match unbeaten run and lifted Lazio into sixth place.
The Romans are two points adrift of Inter Milan, who are fifth and hold the last Europa League qualifying spot.
The visitors were without coach Sinisa Mihajlovic, with the former Lazio player serving a touchline ban.
Samp had the first chance of the game midway through the first half, when Manolo Gabbiadini's bullet strike from the heart of the penalty area went just over the bar.
Two minutes later, Lazio goalkeeper Etrit Berisha kept out Lorenzo De Silvestri's powerful header as the Genoa team pressed forward.
The hosts first tested Angelo Da Costa on the half-hour mark when Candreva's right-footed shot was saved by the keeper.
Lazio went in front before half-time when Keita's cross found an unmarked Candreva in the box and his right-footed shot beat Da Costa.
The home side suffered a setback in the 57th minute when Biglia was handed his marching orders after a late tackle on Nenad Krsticic.
Samp went in search of the equaliser and came close to getting it when Gaetano Berardi's hard drive from 30 yards warmed the hands of Berisha.
Lulic made it 2-0 when he latched onto Stefano Mauri's pass and drilled a right-footed shot from the middle of the box past Da Costa and into the back of the net.
Lazio, who have lost just once at the Stadio Olimpico this year, held on for their 13th win of the campaign.