The Academy Award-nominated actress will return to the HBO fantasy series as Ruby Jean Reynolds, the schizophrenic mother of Lafayette (Nelsan Ellis).
Reynolds was last seen in the third season, where she was taken back to hospital after threatening her son and Jesus (Kevin Alejandro) with a knife.
Woodard was nominated for the 'Outstanding Guest Actress in a Drama Series' award at the 2011 Emmys for her True Blood role.
She will appear in the fifth and sixth episodes of the fifth season, according to Entertainment Weekly.
The fifth season of True Blood premieres on HBO on June 10 and on FX in the UK later this year.
Law & Order: SVU star Christopher Meloni will be among a group of new characters in the latest season.
Watch the trailer for season five below: