The coronavirus is naturally mutating over time and producing new variants. Some of them are more contagious and destructive than previous strains. Also, some variants are capable of therapeutic escaping. Earlier SARS-CoV-2 variants proved that some are supercritical, and newly mutated strains are creating new challenges to the global healthcare systems. Here we aimed to evaluate different coronavirus variants and associated challenges for healthcare systems. We searched for information online and on the PubMed, Scopus, and Embase databases. We found the wild-type virus is more sensitive for neutralization and more controllable than newer variants. The Delta and Omicron variants are more highly transmissible than Alpha, Beta, and Gamma variants. Also, few strains are resistant to neutralization. Therefore, there is a chance of reinfection among the vaccinated population. The transmissibility and resistance of the recently identified Omicron variant is still unclear. The Delta variant is the most dangerous among all variants due to its high transmissibility, disease severity, and mortality rate. For poor and developing countries, oxygen supply, medication, vaccination, and device supply are challenging during epidemic waves. Slowing down the transmission, mass vaccination, vaccine redesign, re-compiling action plans, and following safety guidelines can be effective solutions to the new challenges.