Background. Each year, immunization averts an estimated 2–3 million deaths from diphtheria, tetanus, pertussis, and measles. In 2011, nearly 107 million infants (83%) worldwide received at least 3 doses of DTP vaccine; however, approximately 22.4 million failed to receive 3 doses, and this causes large numbers of children susceptible to vaccine-preventable diseases and death. Nearly 8.4 million received at least 1 DTP dose. The aim of this was to assess coverage, opportunity, and challenges of EPI among children of age 12–23 months in Woldia town, Amhara region, Northeast Ethiopia. Method. In this mixed community-based cross-sectional study, 389 study subjects were selected by using a multistage sampling method. Interviewer-administered structured questioners were used. Data were entered and analyzed using SPSS Version 20 and presented by using tables and figures. Documented/recorded file from the qualitative data were transcribed into word narrative. Finally, it was presented by thematic analysis. Result. A total of 389 mothers/caretakers were interviewed. Based on vaccination card and mothers/caretakers’ recall, 385 (99%) of the children took at least a single dose of vaccine. From total children, 4 (1%) were not immunized at all, 44 (11.3%) were partially immunized, and 343 (87.7%) were fully immunized. The dropout rate was 9% for BCG to measles, 2.4% for Penta1 to Penta3, 8.3% for penta1 to measles, and 1.6% for pcv1 to Pcv3. A qualitative study revealed that workload, shortage of vaccine, and noncompliance of the mother/caretaker for the next scheduled date was the major challenge faced by health professionals and health extension workers. Conclusion. Vaccination coverage was low compared with the Millennium Development Goals target. It is important to increase and maintain the immunization level to the intended target. Thus, the town health office and concerned stakeholders need to work more to improve the performance of the expanded program on immunization in this area.