Zenit are five points clear of second-placed CSKA Moscow with reigning champions Lokomotiv Moscow third, just one point further back.
Zenit manager Sergei Semak has warned his men to take 10th-placed Orenburg seriously after watching his side struggle to a 1-1 draw in their last Premier League match at Spartak Moscow just before the international break.
"We played well since the league resumed from the winter break but we've lost points in our last league game having just two days for recovery after an important Europa League encounter," Semak told Zenit's official site.
"Now, after the break for the international duties we need to refocus completely on the domestic league as winning of the Russian title is now our top priority this season. We can't afford to lose points again."
Semak also said he was hoping that Zenit's Russian international striker Artem Dzyuba, who scored one of the national team's goals in the 4-0 win at Kazakhstan in a Euro 2020 qualifier to end his 15-match goalless drought in all competitions, will be equally deadly against Orenburg.
CSKA Moscow need to bag all three points to keep up the chase when they host lowly Ufa on Sunday.
Coach Viktor Gancharenko said he was pleased with his team's performance in their previous league encounter when they beat Yekaterinburg by a single goal away.
"It was very important for us to convert our dominance into a victory at Yekaterinburg," he said.
"Now I hope my men will do the same in the match with Ufa. But we should be cautious as the matches after the breaks for the international duties often bring surprises."
Gancharenko said he was counting on two of Russia's freshly minted internationals -- midfielder Ilzat Akhmetov, who made his debut for his country in the Euro 2020 qualifier against Belgium this week, and this season's Premier League top scorer Fyodor Chalov, who won his first cap in the match with Kazakhstan -- to maintain their impressive form as the season hots up.
Lokomotiv will have to pass a stern test of their hopes of retaining the title when they visit city rivals Dynamo on Saturday.
The railway-backed side's chief Yury Syomin said he expected a tough battle at Khimki Arena.
"We've struggled this season from the start but it was too early to write us off," he said.
"We've won our last two league matches and played quality football in these games. Dynamo, who have lost their last two league games, are dangerous as they have nothing to lose.
"I'm happy that my players avoided any serious injuries while on international duty and I hope to field a full-strength line-up on Saturday."