Simple SummarySome diseases of dairy cows require the use of an antimicrobial and an anti-inflammatory drug in association to be fully cured and relieve pain. However, pharmacological treatments in cattle are subject to strict regulations and restrictions, and cow handling is not always easy and safe. For these reasons, only the antimicrobial is often administered, thus not fully applying the appropriate therapeutic protocol. This study investigated whether the use of a drug combining ceftiofur and ketoprofen in a single injection instead of ceftiofur alone can improve the healing and welfare of dairy cows affected by a pyretic inflammatory disease, such as acute puerperal metritis. The results show that the variation in the physiological parameters was similar between the two treatment groups, and daily activity and milk yield did not differ from healthy cows. However, affected cows that were treated with the combined drug seemed to be more likely to become pregnant within 120 days in milk than those that received the antimicrobial alone, having an estimated number of days open more similar to that of the healthy cows.This study aimed at investigating the benefits of using a drug combining ceftiofur and ketoprofen in a single injection on dairy cow welfare in the case of inflammatory disease with pyrexia, such as acute puerperal metritis (APM). Cows of an Italian dairy farm were examined between 5 and 14 days of calving: those with APM were randomly treated either with combined ceftiofur–ketoprofen (CD) or ceftiofur alone (C), starting from Day 0, and an equal number of healthy cows served as a control (CTR). Clinical examination and blood sampling were performed until Day 7 in each group according to specific schedules. Daily cow activity was recorded until Day 14 and daily milk production until Day 30. Additional data on fertility were collected until 120 days in milk (DIM). Data of 20 cows per group were analyzed. Body temperature and haptoglobin concentration dropped between Day 0 and 4 in both CD and C, approaching the level of CTR. The cure rate at Day 7 (body temperature < 39.0 °C) was 65 (CD) and 55% (C), without statistical difference. Neither cow activity nor milk production differed among the three groups. Reproductive performances in both CD and C were similar to CTR, but CD cows were 2.8 times more likely to be pregnant within 120 DIM than C, becoming pregnant about 14 days sooner. Both treatments (CD and C) have been effective in bringing the cows back to health conditions (CTR), and further studies would be needed to confirm the positive effect observed for CD on days open of the affected cows.