| Date: | 13–19 September |
| Edition: | 35th |
| Surface: | Hard |
| Location: | Istanbul, Turkey |
| Champs: |  James Duckworth |
| Champd: |  Radu Albot / Alexander Cozbinov |
| Before Year: | 2021 |
| Before Name: | Amex-Istanbul Challenger |
| Main Name: | Amex-Istanbul Challenger |
| After Name: | Istanbul Challenger |
The 2021 Amex-Istanbul Challenger II was a professional tennis tournament played on hard courts. It was the 35th edition of the tournament which was part of the 2021 ATP Challenger Tour. It took place in Istanbul, Turkey between 13 and 19 September 2021.
| Country | Player | Rank1 | Seed | |
|---|---|---|---|---|
| Australia | James Duckworth | 68 | 1 | |
| Moldova, Republic of | Radu Albot | 108 | 2 | |
 Colombia | Daniel Elahi Galán | 110 | 3 | |
 Japan | Yasutaka Uchiyama | 123 | 4 | |
| Australia | Marc Polmans | 148 | 5 | |
 Russian Federation | Evgeny Donskoy | 152 | 6 | |
 Ukraine | Illya Marchenko | 154 | 7 | |
 Egypt |
The following players received wildcards into the singles main draw:
The following players received entry from the qualifying draw:
Nick Chappell
Christopher Heyman
Laurent Lokoli
Aldin ŠetkićThe following player received entry as a lucky loser:
See main article: 2021 Amex-Istanbul Challenger II – Singles.
James Duckworth def. Wu Tung-lin 6–4, 6–2.See main article: 2021 Amex-Istanbul Challenger II – Doubles.
Radu Albot / Alexander Cozbinov def. Antonio Šančić / 
Artem Sitak 4–6, 7–5, [11–9].
