Dr. Steven Shafer, an expert on propofol, said it's impossible for the drug to enter the bloodstream in any sizeable amount if it is swallowed.
He also told jurors it was highly unlikely the singer gave himself a fatal injection of the medication, or swallowed a lethal dose of a sedative.
Coroner's officials determined Jackson died from acute propofol intoxication, and defendant Dr. Conrad Murray has acknowledged giving the singer the drug as a sleep aid.
"The possibility of a direct self-injection seems extremely unlikely," Shafer said, explaining that it would be difficult for Jackson to have time to inject himself based on Murray's timeline of being out of the singer's bedroom only for a few minutes.
Propofol if not mixed with a painkiller is painful, Shafer said. "You would not want to try to inject this into a vein and miss."
He said it was much more likely that Murray gave Jackson a much higher dose of propofol than he told police.
Defense attorneys for Murray said last week they had abandoned the theory that Jackson swallowed propofol. They could begin questioning Shafer later in the day.
Still, the theory was included in a report by their propofol expert, Dr. Paul White, who is expected to testify during the defense case scheduled to being Friday and feature 15 witnesses.
Defense lawyers also have suggested that Jackson swallowed eight lorazepam pills without Murray's knowledge and that may have been enough to kill him.
Shafer, however, said the defense's own testing showed Jackson hadn't swallowed any lorazepam pills in the four hours before his death, and the amount of the medication found in his stomach was "trivial."
Shafer also suggested that Murray probably gave Jackson more of the sedative lorazepam intravenously than he told police.
In addition, prosecutors have said coroner's officials recently conducted tests that showed the levels of lorazepam in Jackson's stomach were far lower than defense attorneys have led jurors to believe.
Regarding oral ingestion of propofol, Shafer on Thursday walked jurors through studies dating back to 1985 on animals and more recently on humans showing propofol that is swallowed wouldn't produce sedation or reach the bloodstream in any sizeable amount.
Murray has pleaded not guilty to involuntary manslaughter. He was Jackson's personal physician for roughly two months before the singer's unexpected death in June 2009.
Shafer told jurors Wednesday that 17 violations of standard practices by Murray each put Jackson's life at risk. Many concerned modern life-saving equipment that Murray lacked when he gave Jackson propofol in the bedroom of his rented mansion, but Shafer said among the cardiologist's worst transgressions was putting his own interests ahead of Jackson.
He compared the Houston-based cardiologist to an employee who wouldn't say no to his boss.
"Saying yes is not what doctors do," he testified.
Shafer, a Columbia University professor and researcher who helped write the guidelines and warnings included with every vial of propofol, repeatedly said Murray's actions were unconscionable, unethical and illegal.
He said Murray's case is unlike any he's ever seen.
"We are in pharmacological never-never land here, something that was done to Michael Jackson and no one else in history to my knowledge," Shafer told jurors.
The professor reminded jurors that Murray had bought more than four gallons of propofol to use on the singer over the course of his employment, talked on the phone in the hours before Jackson's death, and delayed calling 911 when he found the singer unresponsive.
"The worst disasters occur in sedation and they occur when people cut corners," Shafer said. In Jackson's case, "virtually none of the safeguards were in place," he added.
Shafer said he was testifying for the prosecution without a fee because he wants to restore public confidence in doctors who use propofol, which he called a wonderful drug when properly administered.
"I am asked every day in the operating room, `Are you going to give me the drug that killed Michael Jackson,"' Shafer said. "This is a fear that patients do not need to have."
AP Special Correspondent Linda Deutsch contributed to this report.