Dr. Steven Shafer, who presented a number of possible scenarios for Jackson's overdose, said one posed by Dr. Conrad Murray's defense - that the star gave himself the powerful anesthetic - is "crazy."
"He can't give himself an injection if he's asleep," Shafer told jurors.
Shafer took the jury through a virtual chemistry class with diagrams and formulas projected on a large screen. He indicated the residue of drugs found during Jackson's autopsy suggested Murray gave his patient much larger doses of sedatives than he told police.
He also said Jackson would have been extremely groggy from the drugs administered by IV throughout the night.
Murray told police he was away from Jackson for just two minutes - a period during which the defense says the singer could have grabbed a syringe and given himself additional propofol.
"People don't just wake up from anesthesia hell bent to pick up a syringe and pump it into the IV," Shafer said, reminding the jury that the procedure was complicated. "It's a crazy scenario."
He also said it was unlikely that Jackson injected himself with a needle because the pop star's veins were too deteriorated and the procedure would have been extremely painful.
Witnesses have said Jackson knew the drug had to be diluted with lidocaine in an IV to prevent burning when it entered the veins.
Shafer, a leading expert on anesthesiology who teaches at Columbia University Medical School, also rejected the claim that Jackson may have swallowed eight pills of the sedative lorazepam, also known as Ativan, causing his death.
Shafer said the amount of lorazepam found in Jackson's stomach was "trivial" and not linked to oral ingestion. He suggested Murray gave Jackson much more lorazepam by IV infusion than the four milligrams he said he did.
After receiving lorazepam, another sedative known as midazolam (Versed) and propofol, Jackson would have been too groggy to handle the infusion of more anesthetic through an IV pump, Shafer said.
His opinions set up an expected clash with the views of his colleague, Dr. Paul White, who was waiting to testify for the defense. The men have been friends and associates for 30 years.
White, who sat in the courtroom taking notes, has suggested to the defense in a written report that Jackson might have swallowed a vial of propofol, accounting for the high level of the drug in his autopsy.
But the defense announced last week it had abandoned the theory in May after running its own tests that disproved the theory.
Coroner's officials determined Jackson died on June 25, 2009, from acute propofol intoxication, and Murray has acknowledged giving the singer the drug as a sleep aid. The officials cited other sedatives as a contributing factor.
Murray has pleaded not guilty to involuntary manslaughter.
Shafer testified Wednesday that Murray was directly responsible for Jackson's death, citing what he said were 17 "egregious violations" of the standard of care provided by physicians.