This non-comparative prospective case series was conducted to characterize the clinical impact of intense pulsed light (IPL)-based treatment in dry eyes associated to Meibomian gland dysfunction (MGD), defining the predicting factors for a successful outcome with this therapy in a large case series. A total of 390 eyes (195 patients, range: 23–93 years) received four sessions of Optima IPL system (Lumenis, Yokneam, Israel). Significant changes were observed in tear film osmolarity in both eyes (p < 0.001) and in meibum quality (p < 0.001), with more eyes showing clear or yellow secretions after therapy. Mean change in the ocular surface disease index (OSDI) was −8.61, ranging from −27.00 to 11.00. This change was significantly correlated with the baseline value of OSDI (r = −0.489, p < 0.001). The change in osmolarity correlated significantly with the baseline osmolarity in both eyes (right r = −0.636, left r = −0.620, p < 0.001). A linear predicting model of the change in OSDI with therapy was obtained: change OSDI = 10.99 − 0.35 × OSDI − 1.03 × NIBUT_RE-LE (mean non-invasive break up time of right and left eye) − 2.03 × Meibum quality grade (p = 0.001; R²: 0.325). In conclusion, the improvement in symptomatology achieved with an IPL-based therapy can be predicted at baseline using a linear model considering the level of MGD and the magnitude of OSDI and NIBUT (non-invasive break-up time).