She was provisionally suspended from the WTA Tour in 2016 after testing positive for the heart medication meldonium, although she was found to "bear no fault or negligence" by the International Tennis Federation.

In 2022, Lepchenko was suspended from tennis for four years (backdated to August 2021), after testing positive for the stimulant adrafinil, and its metabolite, modafinil.

In 2011 at the French Open, Lepchenko recorded the biggest win of her career by defeating 18th seed Flavia Pennetta, in the first round.

Her next tournament was the Wimbledon Championships, where she defeated Austrian Patricia Mayr-Achleitner, and in the second round, 31st seed and former top-15 player, Anastasia Pavlyuchenkova before she lost against defending champion, Petra Kvitová, 1–6, 0–6.

[15] However, in doubles, she and her partner, Zheng Saisai, reached the semifinals where they lost to Australian wildcards Ashleigh Barty and Casey Dellacqua.

[16] Playing in the Fed Cup tie against Italy, Lepchenko won both of her matches over Roberta Vinci and Sara Errani.

After she was handed a walkover when Julia Görges withdrew due to illness,[25] she was defeated in the third round by seventh seed Sara Errani, in two sets.

6, and after beating qualifier Michelle Larcher de Brito and Tamira Paszek, she lost in the quarterfinals to top seed and eventual finalist, Agnieszka Radwańska.

[40] She played her final tournament of the year at the Kremlin Cup where she lost in the first round to wildcard Alisa Kleybanova, in three sets.

Playing in Indian Wells, Lepchenko reached the third round after wins over qualifier Alison Van Uytvanck and 29th seed Daniela Hantuchová.

[52] Playing at the Italian Open, she was defeated in the third round by top seed, defending and eventual champion, Serena Williams.

She advanced to the semifinals defeating Caroline Garcia, second seed and last year finalist Agnieszka Radwańska, and qualifier and compatriot Sachia Vickery.

[69] Lepchenko twice served for the opening set but Ivanovic came back both times to win the first-set tiebreaker and eventually the match.

[85] Ranked 46 at the US Open, Lepchenko advanced to the fourth round defeating Kirsten Flipkens, Lesia Tsurenko, and Mona Barthel.

Lepchenko began 2016 season at the Brisbane International where she reached the quarterfinal round losing to sixth seed, Carla Suárez Navarro.

Playing in New York at the US Open, Lepchenko reached the third round after beating Peng Shuai and 15th seed Timea Bacsinszky.

[108] Playing in Tokyo at the Japan Women's Open, Lepchenko reached the quarterfinal round where she was defeated by sixth seed Zhang Shuai.

[109] She stayed in Tokyo to compete at the Pan Pacific Open where she lost in the first round to Olympic gold medalist Monica Puig.

[112] Lepchenko played her final tournament of the season at the Luxembourg Open where she lost in the second round to top seed and eventual finalist Petra Kvitová.

[116] Seeded second at the Midland Tennis Classic, Lepchenko made it to the quarterfinal round where she was defeated by Canadian qualifier Katherine Sebov.

Competing in Morocco at Rabat, Lepchenko advanced to the semifinal round where she was defeated by eventual finalist Francesca Schiavone.

Lepchenko played her final tournament before the French Open at the Nürnberger Versicherungscup where she was defeated in the second round by Sorana Cîrstea.

[125] Playing in Spain at the Mallorca Open, Lepchenko lost in the second round to second seed and eventual champion Anastasija Sevastova.

[129] Coming through qualifying at the Rogers Cup, Lepchenko stunned 12th seed and French Open champion Jeļena Ostapenko in the first round.

[136] Sliding past qualifying at the China Open in Beijing, Lepchenko was defeated in the second round by 12th seed Petra Kvitová.

Lepchenko won her first WTA 125 title at the 2021 LTP Women's Open, defeating to Jamie Loeb in the final in three sets.

199 at the 2024 US Open, she qualified for the main draw and made the second round of a major in more than three years after the retirement of Brenda Fruhvirtová,[146] before losing to Anastasia Potapova.

[147] She qualified for the newly upgraded WTA 500 2024 Korea Open, losing to seventh seed Ekaterina Alexandrova in the first round.

She and her family, whose Russian–Ukrainian heritage allegedly made them a target of persecution in their homeland,[149][150] were granted political asylum by the United States.

They had lived in the U.S. for more than five years when Lepchenko began representing the United States in WTA and ITF tournaments,[149] later also at the 2012 Summer Olympics.