In this study, phosphate/thermal activated peroxymonosulfate (PMS) process were applied to degrade the antiviral drug acyclovir (ACV) in water. Both Na2HPO4 and Na5P3O10 could effectively enhance ACV removal by thermally activated PMS process and the enhancement of Na2HPO4 was more significant. High reaction temperature favored ACV removal and the best removal can be achieved at a certain PMS dosage in both processes. With increasing Na2HPO4 dosage, the ACV removal first increased and then decreased, while increasing Na5P3O10 dosage caused the enhancement of the degradation. The ACV degradation by Na2HPO4/thermal/PMS system was easily affected by initial solution pH, while Na5P3O10/thermal/PMS system operated in a wider pH range. The addition of Cl- and NO3- exerted insignificant effect in Na2HPO4/thermal/PMS process, while posed complicated impact by Na5P3O10/thermal/PMS process. The presence of HA significantly retarded ACV degradation by Na2HPO4/thermal/PMS system, while in Na5P3O10/thermal/PMS system, high HA concentration accelerated the degradation. In Na2HPO4/thermal/PMS system, SO4•- and •OH were identified as the main active species. Whereas, the ACV degradation was relied on non-free radicals (1O2) in Na5P3O10/thermal/PMS process. The strengthening effect of Na2HPO4 was reflected in its ability to reduce the reaction energy barrier required for O-O bond cleavage in PMS molecules, while Na5P3O10 provided an alkaline condition for the self-decomposition of PMS. 10 and 11 intermediate products were detected in Na2HPO4/thermal/PMS and Na5P3O10/thermal/PMS systems, respectively. Both processes produced intermediates with higher toxicity than ACV according to software analysis.