Countries which currently recommend it are being urged to revise their guidelines.
Lopinavir-ritonavir showed "no beneficial effect" in hospitalised patients not on ventilators, according to the University of Oxford's Recovery trial - the world's largest randomised clinical trial of potential Covid-19 treatments.
Many countries which currently recommend the drug should revise their guidelines in the wake of the results, experts said, as they pulled the medication from the trial.
Some 1,596 patients were randomised to receive the drug and were compared with 3,376 patients randomised to receive standard hospital care, researchers said.
Of these patients, some 4% required invasive mechanical ventilation when they entered the trial, 70% required oxygen alone, and 26% did not require any respiratory intervention.
The results showed "no significant difference in the primary endpoint of 28-day mortality" (22.1% lopinavir-ritonavir v 21.3% usual care), the Recovery trial said.
The trial researchers added: "The results were consistent in different subgroups of patients.
"There was also no evidence of beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay.
"These data convincingly rule out any meaningful mortality benefit of lopinavir-ritonavir in the hospitalised Covid-19 patients we studied."
Professor Martin Landray from Oxford's Nuffield Department of Population Health, and deputy chief investigator of the Recovery trial, said: "These are clear results and once again emphasise the value of large randomised clinical trials in differentiating drugs we hope work from treatments we know do work.
"In many countries, current guidelines recommend lopinavir-ritonavir as a treatment for Covid-19.
"The results from this trial, together with those from other large randomised trials, should inform revisions to those guidelines and changes to the way individual patients are treated."
However, researchers added: "We were unable to study a large number of patients on invasive mechanical ventilation because of difficulty administering the drug to patients on ventilators.
"As such, we cannot make conclusions about the effectiveness in mechanically ventilated patients.
"Full results will be made available as soon as possible."
More than 11,800 patients from 176 NHS hospitals have been randomised to receive different potential treatments for the Recovery trial.
So far, the results have also shown another medication, hydroxychloroquine, to be ineffective.
US President Donald Trump has previously said he had been taking the anti-malarial drug to prevent coronavirus.
However, low-dose dexamethasone, a type of steroid, was found to reduce the risk of death by about one third among patients receiving ventilation and by one fifth in those requiring oxygen alone, trial results suggest.
But it showed no benefit among those not requiring respiratory support, researchers added.
Professor Fiona Watt, executive chairwoman of the Medical Research Council, which helped fund the trial, said: "It is very important that we test potential therapies in randomised clinical trials so that we can find out whether repurposed drugs work or not.
"Whilst it is disappointing that lopinavir-ritonavir, like hydroxychloroquine, has been found to be ineffective, the earlier findings with dexamethasone were positive.
"Researchers and health professionals are now focusing their efforts, and patient care, on other promising drugs."
The dexamethasone results are currently under peer review, with the results for the hydroxychloroquine and lopinavir-ritonavir treatments being prepared for submission.
Trials for other potential treatments, including azithromycin, tocilizumab and convalescent plasma, are ongoing.