Doxycycline (DOXY) is a second-generation tetracycline with anti-inflammatory and neuroprotective effects. A proinflammatory profile seems to predict the severity of depressive symptoms. In the present study, we aimed at determining whether the anti-inflammatory action of subantimicrobial-dose doxycycline (SDD) (DOXY, 10mg/kg), alone or combined with the antidepressant escitalopram (ESC), could revert lipopolysaccharide-induced depressive-like alterations in mice. Male Swiss mice received saline or lipopolysaccharide (LPS) for ten consecutive days. From the 6^th day of LPS exposure, they were treated with DOXY 10 mg/kg, ESC 4 mg/kg, DOXY 10 mg/kg plus ESC 4 mg/kg (DOXY+ESC), or saline. On the 10^th day, we assessed behavioral despair (forced swimming test), anhedonia (sucrose preference test), brain oxidative stress markers, and inflammatory and protective pathways related to depression, such as NF-kB and phospho-CREB. Our results showed that DOXY alone or combined with ESC reduced hippocampal Iba-1 expression and interleukin (IL)-1β levels. Only DOXY+ESC successfully reversed the LPS-induced increase in NF-kBp65 expression and TNFα levels. DOXY caused a marked increase in the hippocampal expression of phospho-CREB and GSH concentrations. DOXY and DOXY+ESC showed a tendency to modulate the functional status of mitogen-activated kinase p42-44 (Phospho-p44/42 MAPK) and of the phosphorylated form of glycogen synthase kinase 3 beta (GSK3β), revealing a protective profile against inflammation. In conclusion, SDD, combined with ESC, seems to be a good strategy for reverting inflammatory changes and protecting against depression.