In his closing speech, prosecutor Richard Wright KC told jurors the couple were the "only two candidates" and there was "no doubt Isabelle was murdered".
The jury has heard Walker called 999 on 13 September, with paramedics finding Isabelle collapsed at the foot of the stairs without a pulse.
She died in hospital the following day.
Isabelle was found to have a fractured skull and catastrophic brain injury, Wright said, and there was "incontrovertible proof" she had been sexually assaulted.
She was "covered in bruises" and it was discovered she had suffered 21 broken bones including in both legs, her arm and "just about every vertebrae in her spine" in the weeks before her death, the court heard.
Walker began a relationship with Simpson last summer and "became a facilitator" of his "sexual abuse of her daughter", the prosecutor said.
Wright said a video on 7 June showed Isabelle as a "happy, healthy and mischievous two-year-old", but 99 days later she was dead.
"This was no accident," the prosecutor said, with her final fatal head injury akin to a multi-storey fall or a high-speed car crash.
He said Isabelle's plethora of injuries went back weeks showing it was not a case of "just one less of temper" from a "frazzled and exhausted parent who lashes out and regrets it".
It was a "persistent and wicked campaign of serious violence being done to a completely defenceless child", Wright said.
There was "no doubt Isabelle was murdered" as those "waging that campaign of violence against her" could only have been intending to harm her, the court heard.
"That little girl was murdered, sexually assaulted, subjected to cruelty and neglect," the prosecutor said, adding there were "only two candidates".
"The thing that changed, that set in train this calamitous decline from a happy healthy child to [a victim of] sexual abuse, gross and repetitive violence and murder was the introduction by Alexandra Walker into her life, and that of her child, of Harrison Simpson," Wright said.
Their relationship "created the conditions in which that little girl could be abused so terribly" and in a "final cruel and savage attack" be murdered, jurors were told.
Isabelle's world was "turned completely on its head" with the final weeks of her short life spent in pain, fear and "bewilderment", the prosecutor said.
Wright said the couple, who were cannabis dealers, were drinking and taking drugs the night Isabelle was fatally injured, and the attack "can only have happened when both of them were in that tiny house together".
Walker was an "attention-seeker" who "barely knew Simpson from Adam" but "decided the relationship was more important than the safety of her daughter", the jury heard.
He said it "must have been completely obvious from an early stage" Isabelle was being seriously injured but Walker delayed getting medical treatment to avoid having to answer questions.
Walker had expressed suspicions Simpson was sexually interested in her daughter, as evidenced by her searching online to see if was on a child abuse register, and yet she still left her two-year-old alone with him, the court heard.
There was also "good evidence" each of the two defendants had injured Isabelle in the weeks before her death, Wright said.
The "failure to intervene" and seek treatment for Isabelle's "obvious" injuries "demonstrates they were in this together", the prosecutor said.
When Walker did eventually take her daughter to doctors, she complained NHS staff "doing the job she should have been of protecting" Isabelle were unfairly persecuting her, the prosecutor said.
He also said Simpson's refusal to give evidence at the trial was "plain evidence he did murder Isabelle" and thought by remaining silent he "might just get away with he did".
