The Magpies' number nine was an unused substitute in the Boxing Day defeat at Liverpool, but will lead the line at Vicarage Road as Rafa Benítez's side look to complete a Premier League double over the Hornets, who started the day in tenth.
Joselu makes way for Rondón while Christian Atsu also comes back into the side after missing the trip to Anfield, replacing Kenedy, and Ayoze Pérez is restored to the starting XI in place of Yoshinori Muto.
Jonjo Shelvey returns to the squad after a thigh injury - his last start came in November's 1-0 win against Javi Gracia's men - but he is named among the substitutes.
Martin Dúbravka, who saved a penalty in this fixture at the end of last season, starts in goal. DeAndre Yedlin, Federico Fernández, Jamaal Lascelles, Paul Dummett and Matt Ritchie form a five-man defence.
Isaac Hayden continues alongside Mohamed Diamé in midfield with Atsu and Pérez - who scored the winner against Watford at St. James' Park - playing behind Rondón.
Shelvey is joined on the bench by Javier Manquillo, Fabian Schär, Jacob Murphy, Joselu, Muto and goalkeeper Freddie Woodman.
Newcastle United: Martin Dúbravka, DeAndre Yedlin, Federico Fernández, Jamaal Lascelles (c), Paul Dummett, Matt Ritchie, Isaac Hayden, Mohamed Diamé, Christian Atsu, Ayoze Pérez, Salomón Rondón
Substitutes: Freddie Woodman, Javier Manquillo, Fabian Schär, Jacob Murphy, Jonjo Shelvey, Joselu, Yoshinori Muto