This study evaluated the impact of COVID-19 and other factors on the health-related quality of life (HRQoL) of Saudi patients during infection and after recovery using the EQ-5D-5L and EQ-VAS instruments. An observational prospective study was conducted in November 2022, during which 389 COVID-19 patients were surveyed during their visit to a medical center. Two weeks after their recovery, they were contacted again to re-evaluate their HRQoL (192 patients either refused to participate or withdrew). The mean of the EQ-5D-5L index and EQ-VAS scores significantly increased from (0.69 ± 0.29 and 63.16 ± 24.9) during infection to (0.92 ± 0.14 and 86.96 ± 15.3) after recovery. Specifically, COVID-19 patients experienced improvement of several HRQoL dimensions post recovery, such as better mobility, enhanced self-care, returning to usual activities, less pain/discomfort, and alleviated anxiety/depression. Multiple linear regression analyses showed that having a normal weight, being employed, not being anemic, and previously taking the BCG vaccine were positively associated with a greater change in the HRQoL. An interaction between being asthmatic and taking the influenza vaccine positively predicted a lower change in the HRQoL. Having a normal weight positively predicted a greater change in the perceived health state after recovery. Increasing the consumption of natural supplements (honey and curcuma) did not improve the HRQoL or the perceived health state. Based on these findings, COVID-19 mildly impacted the HRQoL of Saudis with varying effects depending on some socio-demographic/clinical characteristics of the patients.