Radwanska, who had seen off Francesca Schiavone of Italy 6-4 6-3 in the previous round, found her American opponent a far tougher nut to crack.
The world number four was pushed all the way in the opening set and faced nine break points, saving six, but crucially losing three on the way to a tie-break. The Pole managed to ease through that though, taking it with the loss of just two points.
However, Tashkent-born Lepchenko took encouragement from her performance in the first set and, with both players upping their services games, the 27-year-old claimed the second after breaking just once - the only time either player managed to do so in the set.
Nothing could separate the two players until Radwanska broke in the eighth game of the third to go 5-3 ahead. She then served out to seal victory.
Radwanska, seeking her third WTA title of the season, will play another American, Jamie Hampton, for a place in the final. Fourth seed Hampton downed Russia's Vera Dushevina 6-4 6-3 to book her place in the last four.
In the day's other quarter-finals, third seed Dominika Cibulkova of Slovakia beat Radwanska's sister Urszula, seeded seventh, 7-5 6-3 to set up a match with Sorana Cirstea of Romania, the fifth seed who saw off Belarusian Olga Govortsova 6-3 6-2.
Stanford Classic results
1-Agnieszka Radwanska (Poland) beat 6-Varvara Lepchenko (U.S.) 7-6(2) 3-6 6-3
4-Jamie Hampton (U.S.) beat Vera Dushevina (Russia) 6-4 6-3
3-Dominika Cibulkova (Slovakia) beat 7-Urszula Radwanska (Poland) 7-5 6-3
5-Sorana Cirstea (Romania) beat Olga Govortsova (Belarus) 6-3 6-2