Introduction Multiple births constitute the dominant adverse effect of fertility treatments and are associated with increased perinatal risks. The aim of this study was to comprehensively examine and present time trends in multiple births in Greece. Methods Data on live births by multiplicity were derived from the Hellenic Statistical Authority, covering a 65-year period from 1957 to 2021. Temporal trends in multiple birth rates (MBR), twin birth rates (TwBR), as well as in triplet and higher-order birth rates (Tr+BR) were assessed using joinpoint regression analysis, and the annual percentage changes (APC) were calculated with a 95% confidence interval (95% CI) and level of statistical significance (p < 0.05). Results The MBR in Greece showed a downward trend from 1957 to 1979 (APC = -1.7, 95% CI: -2.0 to -1.4, p < 0.001). However, the rate started to climb in the 1980s, accelerated during the 1990s, and continued to rise in the two most recent decades, reaching a historic high and a world record of 57.2 per 1,000 births in 2021, i.e., a 3.4-fold increase since 1985. The TwBR increased from an all-time low of 16.5 per 1,000 births in 1978 with APC = 1.4 (95% CI: 0.2 to 2.5, p = 0.021) during 1979-1989, APC = 6.3 (95% CI: 5.5 to 7.2, p < 0.001) during 1989-2001, and APC = 1.2 (95% CI: 0.8 to 1.5, p < 0.001) during the last two decades (2001-2021). The Tr+BR, after an all-time low of 17.5 per 100,000 births in 1966, increased dramatically from 1982 to 2000 (APC = 12.4, 95% CI: 9.6 to 15.2, p < 0.001), leveled off during 2000-2011, and after reaching a historic maximum of 351.1 per 100,000 births in 2010, there was a sharp decreasing trend during the last decade (2011-2021: APC = -12.1, 95% CI: -16.8 to -7.2, p < 0.001). Conclusion The dramatic increases in maternal age as well as in medically assisted conceptions have resulted in an epidemic increase in MBR in Greece reaching world record levels. During the last decade, there was an encouraging decline in the Tr+BR; however, the TwBR has continued to trend upwards.