The Portugal forward was named as the winner of the 2013 FIFA Ballon d'Or on Monday, and capped that achievement by scoring his 30th goal of the season as Madrid moved into the quarterfinals of the Copa del Rey with a 2-0 win at Osasuna, a game that saw fullback Fabio Coentrao dismissed late in the second half.
The onus is likely to be on the former Manchester United man in Seville, where Real can keep pace with title rivals Barcelona and Atletico Madrid by atoning for its loss at Estadio Benito Villamarin last season and deepen the misery surrounding La Liga's bottom club.
Betis secured a 1-0 home win over the capital club last season thanks to a first-half goal from Benat - now at Athletic Bilbao, who dumped the club out of the Copa del Rey during the week.
However, 32-time Spanish champion Madrid has since recorded consecutive league victories over the Andalusians, who are enduring a season that has been markedly different to its last campaign, when the club finished seventh.
Indeed, Betis has taken just two wins from 19 league games and appear poised for an uphill battle to avoid relegation to the second tier.
Betis has not won a league game since the 1-0 defeat of Villarreal in September last year, with the appointment of Juan Carlos Garrido - brought in to replace Pepe Mel in December - having little impact on results.
The home side faces a difficult challenge if Garrido is to witness his first win as coach against a visiting side which has not lost since the 2-1 Clasico defeat at Barcelona in October.
Suspended midfielder Nono joins long-term absentee Xavi Torres on the Betis injury list, which also features Nosa Igiebor (hamstring) and Alvaro Vadillo (thigh), while midfielder Joan Verdu is a doubt due to illness.
Striker Alvaro Morata sustained an eye injury against Osasuna and could miss out for the visiting side, which remains without Raphael Varane and Sami Khedira due to knee problems.