| Champ: |  Novak Djokovic |
| Runner: |  Andy Murray |
| Score: | 6–2, 3–6, 6–3 |
See main article: 2016 Mutua Madrid Open.
Novak Djokovic defeated the defending champion Andy Murray in the final, 6–2, 3–6, 6–3, to win the men's singles tennis title at the 2016 Madrid Open. It was Djokovic's second title in Madrid and his record 29th ATP Masters 1000 title.
The top eight seeds receive a bye into the second round.