COVID-19 management still lacks a protocol of proven efficacy, and we present a novel COVID-19 immunomodulatory protocol based on our early pioneering article, re-purposing nitazoxanide/azithromycin combination for early COVID-19 diseases. Our findings were followed by two articles to justify the addition of non-steroidal anti-inflammatory drugs to nitazoxanide/azithromycin. Furthermore, another recent article of ours illustrated the potential immunomodulatory mechanisms by which all the drugs used in this manuscript might be beneficial for COVID-19 patients. We presented a case series of 34 confirmed and highly suspected COVID-19 patients. It is noteworthy that 13 PCR-confirmed COVID-19 patients were included while the others were diagnosed by other measures and all cases were managed by telemedicine. The patients included adult males and females as well as children. All patients have received a short 5-day-regimen of NSAIDs / nitazoxanide/ azithromycin +/- cefoperazone either in full or in part. The primary endpoint of this protocol was a full relief of all debilitating COVID-19 clinical manifestations, and it was fully achieved within two weeks. Most of the patients who were treated early have fully recovered during their described five days; the leucocytic/lymphocytic counts were significantly improved for those with prior abnormalities. Neither significant adverse effects nor post/para COVID-19 syndrome was reported. In conclusion, we present a pioneering 5-day protocol for the safe and effective treatment of COVID-19 using economic FDA-approved immunomodulatory drugs. We recommend conducting double-blind, randomized clinical trials with sufficient strength at the earliest opportunity.