The 34-year-old Californian, a 17-game winner as recently as 2008, has gone 0-4 with two no-decisions in six outings since a 5-1 win at Milwaukee on April 24.
Lilly has pitched at least six innings in six of seven starts and allowed three earned runs or less five times.
He is 4-3 in 14 career games - 12 starts - against the Pirates with a 4.38 earned run average in 78 innings.
For Pittsburgh, righty Jeff Karstens returns to a starting role for the first time since May 8.
The former New York Yankees draft pick was 1-1 with a no-decision in three starts to begin the season before making six consecutive relief appearances between May 11 and May 27.
He allowed four hits and a run in a four-inning role on May 27 at Cincinnati in his last appearance, lowering his ERA from 5.14 to 4.78.
The Pirates are 2-7 in games he's pitched.
Karstens is 2-1 in four lifetime meetings with the Cubs, including three starts.
In Monday's opener, Bobby Crosby knocked in the go-ahead run with a single in the eighth inning, as the Pirates edged Chicago, 2-1.
Garrett Jones went 2-for-4 with a solo homer and two runs scored for the Pirates, who snapped a five-game skid.
Ross Ohlendorf had his best outing of the season, giving up one run on three hits in a season-high seven innings. He also fanned a season-best six batters and walked two, but remains winless in six starts. Evan Meek (3-1) pitched a scoreless eighth to pick up the win.
Geovany Soto drove in the lone run for the Cubs, who have dropped four straight games in Pittsburgh within the same season for the first time since 1996 (July 3-Sept. 22). Chicago has lost six of its seven matchups with the Pirates this season.
The Pirates have won six of seven versus the Cubs this year, sweeping a three- game home set from May 4-6.